Novel betulinic proline imidazole derivatives as hiv inhibitors

ABSTRACT

The invention relates to novel betulinic proline substituted derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.

This application claims the benefit of Indian provisional application no 3117/CHE/2014 filed on 26 Jun. 2014 which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel betulinic proline substituted derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.

BACKGROUND OF THE INVENTION

The Human Immunodeficiency Virus (HIV) has now been established as the causative agent of the Acquired Immunodeficiency Syndrome (AIDS) for over 20 years (Science 1983, 220, 868-871; N. Eng. J. Med. 1984, 311, 1292-1297). AIDS is characterized by the destruction of the immune system, particularly of CD4+T-cells. HIV is a retrovirus, and the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus to the host cell membrane and finishing with the release of progeny virons from the cell.

The natural compound betulinic acid, isolated from Syzygium clavifolium and several other plant species was found to possess anti-HIV activity. Chemical modifications were undertaken by several research groups in an attempt to identify potent anti-HIV agents by making semi-synthetic analogs of betulinic acid, leading to the discovery of bevirimat as a compound with a novel mechanism of action (J. Nat. Prod. 199457(2):243-7; J. Med. Chem. 1996, 39(5), 1016). Further studies shown that bevirimat acts by disrupting Gag processing (Proc. Natl. Acad. Sci. USA 2003, 100(23):13555-60; Antimicrob. Agents. Chemother. 2001, 45(4), 1225-30; J. Virol. 2004, 78(2): 922-9; J. Biol. Chem. 2005, 280(51):42149-55; J. Virol. 2006, 80(12): 5716-22) and to be a first-in-class maturation inhibitor with a potent activity against HIV-1. Bevirimat went up to phase 2 clinical trials, in clinic despite optimal plasma concentrations, not all patients given bevirimat have a robust viral load reduction. It was reported that non-respondent patients had more frequent base line Gag polymorphisms near the capsid SP-1 cleavage site than responders. HIV gag polymorphism determines treatment response to bevirimat (XVII international HIV drug resistance work shop Jun. 10-14, 2008, Sitges, Spain).

Encouraged by these developments, medicinal chemists started exploring betulinic acid derivatives and related compounds intensively for their therapeutic activities. For example, WO 2014/105926 describes novel betulinic acid proline derivatives as HIV inhibitors; WO 2013/160810 describes novel betulinic acid derivatives as HIV inhibitors; Journal of Medicinal Chemistry (2012), 55(18), 8128-8136 describes Novel C-28 modified bevirimat analogues as potent HIV maturation inhibitors; WO 2011/153319 describes C-28 amides of modified C-3 betulinic acid derivatives as HIV maturation inhibitors; WO 2011/153315 describes modified C-3 betulinic acid derivatives as HIV maturation inhibitors; WO 2011/007230 describes lupeol-type triterpene derivatives as antivirals; WO 2010/132334 describes 3, 28-disubstituted betulinic acid derivatives as anti-HIV agents; Journal of Medicinal Chemistry (2009), 52(10), 3248-3258 describes Design, Synthesis, Metabolic Stability Assessment, and Antiviral Evaluation of Novel Betulinic Acid Derivatives as Potent Anti-Human Immunodeficiency Virus (HIV) Agents; WO 2009/082819 describes novel lupane derivatives; WO 2009/100532 discloses novel 17 β lupine derivatives as anti-HIV agents; Bioorganic & Medicinal Chemistry Letters Volume 18, Issue 24, 15 Dec. 2008, Pages 6377-6380 describes triterpene based compounds with potent anti-maturation activity against HIV-1; The patent publication WO 2008/057420 describes extended triterpene derivatives as antiretroviral agents; WO 2007/141391 describes betulin derived compounds useful as antiprotozoal agents; WO 2007/141390 describes preparation of betulin derived compounds as antiviral agents; WO 2008/127364 describes preparation of betulinic acid derivatives for use in antiviral and anticancer pharmaceutical compositions; US 2008/0207573 describes preparation of triterpene derivatives for therapeutic use in the treatment of viral infections; WO 2007/141389 describes preparation of betulin derived compounds as antibacterial agents; US 2004/0204389 describes anti-HIV agents with dual sites of action; WO 2007/002411 describes antiviral compounds; CN 1861627 describes antitumor agents; WO 2006/053255 describes novel betulin derivatives, preparation and use thereof; WO 2009/082818 describes novel C-21 keto lupine derivatives preparation and use thereof; and WO 2006/105356 describes methods of manufacturing bioactive 3-esters of betulinic aldehyde and betulinic acid.

Some additional references disclose betulinic acid related compounds. For example, WO 2007/141383 describes betulin derivatives as antifeedants for plant pests; U.S. Pat. No. 6,670,345 describes use of betulinic acid and its derivatives for inhibiting cancer growth and process for the manufacture of betulinic acid; WO 2002/091858 describes anxiolytic marcgraviaceae compositions containing betulinic acid, betulinic acid derivatives, and methods of preparation and use; WO 2000/046235 describes preparation of novel betulinic acid derivatives for use as cancer growth inhibitors; WO 2007/141392 describes cosmetic and pharmaceutical compositions comprising betulonic acid and betulin derivatives; and Pharmaceutical Chemistry Journal, 2002, 36(9), 29-32 describes synthesis and anti-inflammatory activity of new acylated betulin derivatives.

Given the fact of the world wide epidemic level of AIDS, there is a strong continued need for new effective drugs for treatment of HIV infected patients, disease conditions and/or disorders mediated by HIV by discovering new compounds with novel structures and/or mechanism of action(s).

SUMMARY OF THE INVENTION

The present invention relates to the compounds of the formula (1):

wherein,

R₁ can be substituted or unsubstituted alkyl, substituted or unsubstituted aryl,

(wherein R_(b) can be H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);

R₂ can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aminoacids, substituted or unsubstituted alkoxy or substituted or unsubstituted cycloalkyl;

X can be absent, O, S, CH₂ or NR_(a) (wherein Ra can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or Ra can be with their adjacent N and Carbon together form N-contained heterocycle (Preferably, pyrrolidine, piperdine, piperzine, or morpholine);

R₃ and R₄ can be independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted aminoacids and preferably amino acids are substituted by substituted or unsubstituted alkyl, phosphoric acid, or phosphorus prodrugs or R₃ and R₄ can be together with their adjacent carbons to form a bond or R₃ and R₄ can be together with their adjacent carbons to form cyclopropyl or R₃ and R₄ can be together with their adjacent carbons to form epoxide;

W can be C(O), C(S), or CR₇R₈;

R_(x) can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl and specifically heterocycles are imidazoles, oxazoles, oxadiazoles, triazoles, thiazoles, thiadizoles, isothiazoles, isothiadiazoles, pyridines, pyrazines, pyrimidines, or pyridazines;

R_(c) can be hydrogen or substituted or unsubstituted alkyl;

R₆ can be independently selected from H, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy; R and R₆ on different carbon atoms to form a bond;

R₅, R₇ and R₈ can be independently selected from H, CO₂R_(d) (wherein R_(d) can be H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl;

n can be an integer from 1 to 3.

Pharmaceutically acceptable salts of the compounds of the formula (1) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (1) are contemplated.

It should be understood that the formula (1) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof which may be contemplated from the chemical structure of the genus described herein.

It should be understood that the formula (1) structurally encompasses all tautomers.

Also contemplated are prodrugs of the compounds of the formula (1), including ester prodrugs.

According to one embodiment, there is provided a compound of formula (1), wherein Rx is substituted or unsubstituted oxadiazole, substituted or unsubstituted oxazole, substituted or unsubstituted imidazole and substituted or unsubstituted triazole. Most specifically the substituents are isopropyl, t-butyl, substituted or unsubstituted phenyl, pyridine, and thiophene.

According to one embodiment, there is provided a compound of formula (1), wherein R₁ is

According to one embodiment, there is provided a compound of formula (1), wherein R₂ is H.

According to one embodiment, there is provided a compound of formula (1), wherein X is absent.

According to one embodiment, there is provided a compound of formula (1), wherein R₃ and R₄ are together with their adjacent carbons form cyclopropyl.

According to one embodiment, there is provided a compound of formula (1), wherein R₃ and R₄ are together with their adjacent carbons form a bond.

According to one embodiment, there is provided a compound of formula (1), wherein R₃ and R₄ is hydrogen.

According to one embodiment, there is provided a compound of formula (1), wherein R₅ is H.

According to one embodiment, there is provided a compound of formula (1), wherein W is C(O).

According to one embodiment, there is provided a compound of formula (1), wherein n is 1.

Accordingly, one other aspect of the present invention provides compounds of formula (1A):

wherein,

R₁ can be H, substituted or unsubstituted alkyl,

(wherein R_(b) can be H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);

R₂ can be H, substituted or unsubstituted alkyl, substituted or unsubstituted aminoacids, substituted or unsubstituted alkoxy or substituted or unsubstituted cycloalkyl;

X can be absent, O, S, CH₂, or NR_(a) (wherein R_(a) can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or R_(a) can be with their adjacent N and Carbon together form N-contained heterocycle (Preferably, pyrrolidine, piperdine, piperzine, or morpholine);

R₃ and R₄ can be independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted aminoacids and preferably amino acids are substituted by to substituted or unsubstituted alkyl, phosphoric acid, or phosphorus prodrugs or R₃ and R₄ can be together with their adjacent carbons to form a bond or R₃ and R₄ can be together with their adjacent carbons to form cyclopropyl or R₃ and R₄ can be together with their adjacent carbons to form epoxide;

W can be C(O), C(S), or CR₈R₉;

R₆ can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl and most preferably alkyl is methyl, ethyl, isopropyl, and t-butyl, most preferably aryl is substituted or unsubstituted phenyl, most preferably heteroaryl is pyridine and R is preferably substituted or unsubstituted isopropyl, t-butyl, phenyl, pyridine, pyrazine, pyrimidine or chromene;

R₅, R₈ and R₉ can be independently selected from H, CO₂R_(d) (wherein R_(d) can be H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl;

R₇ can be independently selected from H, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;

‘n’ can be an integer from 1 to 3.

Pharmaceutically acceptable salts of the compounds of the formula (1A) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (1A) are contemplated.

It should be understood that the formula (1A) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof which may be contemplated from the chemical structure of the genus described herein.

It should be understood that the formula (1A) structurally encompasses all tautomers.

Also contemplated are prodrugs of the compounds of the formula (1A), including ester prodrugs.

According to one embodiment, there is provided a compound of formula (1A), wherein R₁ is

According to one embodiment, there is provided a compound of formula (1A), wherein R₂ is H.

According to one embodiment, there is provided a compound of formula (1A), wherein X is absent.

According to one embodiment, there is provided a compound of formula (1A), wherein R₃ and R₄ are together with their adjacent carbons form cyclopropyl.

According to one embodiment, there is provided a compound of formula (1A), wherein R₃ and R₄ are together with their adjacent carbons form a bond.

According to one embodiment, there is provided a compound of formula (1A), wherein R₃ and R₄ is hydrogen.

According to one embodiment, there is provided a compound of formula (1A), wherein R₅ is H.

According to one embodiment, there is provided a compound of formula (1A), wherein R₆ is substituted or unsubstituted phenyl and pyridine.

According to one embodiment, there is provided a compound of formula (1A), wherein R₇ is 2-methoxyethoxyl.

According to one embodiment, there is provided a compound of formula (1A), wherein W is C(O).

According to one embodiment, there is provided a compound of formula (1A), wherein n is 1.

Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention (Nomenclature has been generated from Chem. Draw Ultra 11.0 version):

-   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)     pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 1), -   (1R,3S)-3-((((1R,3aS,5aR,5     bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 2), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)     pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 3), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 4), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-ethoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 5), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 6), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11b,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy)-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 7), -   (11R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 8), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 9), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11bR,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy)-2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 10), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 11), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)oxazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)     icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 12), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-methyl-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 13), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-isopropyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 14), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyloxazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 15), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(tert-butyl)oxazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 16), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(4-phenyloxazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 17), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 18), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-chloro     phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 19), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 20), -   (1R,3R)-2,2-dimethyl-3-(2-oxo-2-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)ethyl)cyclo     butane-1-carboxylic acid (Compound 21), -   2,2-di     methyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)-icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclopropane-1-carboxylic     acid (Compound 22), -   2-methyl-2-(4-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)phenoxy)propanoic     acid (Compound 23), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 24), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(3-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 25), -   (1R,3S)-3-((((1R,3a,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 26), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 27), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(3-chloro     phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 28), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-hydroxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl     cyclobutane-1-carboxylic acid (Compound 29), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-iso     propoxy-2-(4-phenyl-1H-imidazol-2-yl)     pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 30), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(tert-butyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 31), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-methoxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 32), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-methoxypyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 33), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5b,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)     pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 34), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4,5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 35), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)     icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 36), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-benzo -   [d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 37), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 38), -   2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic     acid (Compound 39), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-oxobutanoic     acid (Compound 40), -   5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)     icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic     acid (Compound 41), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bS)-1-(1,2-dihydroxypropan-2-yl)-5a,5b,8,8,11a-pentamethyl-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)     icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 42), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxy     ethoxy)-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 43), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,1bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo     butanoic acid (Compound 44), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo     butanoic acid (Compound 45), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-methoxy     phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 46), -   2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic     acid (Compound 47), -   2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic     acid (Compound 48), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 49), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 50), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b, -   8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 51), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 52), -   3-(2-((S)-1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-(((1S,3R)-3-carboxy-2,2-dimethylcyclobutane-1-carbonyl)oxy)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine-1-oxide     (Compound 53), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)     carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid (Compound 54), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)     carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid (Compound 55), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 56), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-(4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 57), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 58), -   (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic     acid (Compound 59), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 60), -   (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic     acid (Compound 61), -   2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic     acid (Compound 62), -   3,3-dimethyl-5-oxo-5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)     pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)pentanoic     acid (Compound 63), -   5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic     acid (Compound 64), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 65), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 66), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 67), -   2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-(4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic     acid (Compound 68), -   4-(((1R,3aS,5aR,5     bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 69), -   5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic     acid (Compound 70), -   4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-penta     methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic     acid (Compound 71), -   5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic     acid (Compound 72), or     pharmaceutically acceptable salts, solvates, including hydrates and     prodrugs of compounds are also contemplated.

The present invention also provides a pharmaceutical composition that includes at least one compound as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, or other container.

The compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.

The present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject one or more compounds described herein in a therapeutically effective amount to cause that infection, specifically in the form of a pharmaceutical composition.

Also provided herein are processes for preparing compounds described herein.

The invention provides a method for preventing; ameliorating or treating a HIV mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. The invention further provides a method, wherein the HIV mediated disease, disorder or syndrome is like AIDS, AIDS related complex, or a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss, or an retroviral infection genetically related to AIDS.

Anti HIV inhibitory potential of the compounds of present invention may be demonstrated by any one or more methodologies known in the art, such as by using the assays described in Mossman T, December 1983, Journal of immunological methods, 65 (1-2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides betulinic proline substituted derivatives and related compounds, which may be used as antiviral particularly as anti-HIV compounds and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers of the derivatives, together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by viral infections, are also provided.

The Following Definitions Apply to the Terms as Used Herein:

The term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

The term “alkoxy” refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon and hydrogen atoms, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., methyloxy, ethyloxy, n-propyloxy, 1-methylethyloxy (isopropyloxy), n-butyloxy, n-pentyloxy, and 1,1-dimethylethyloxy (t-butyloxy).

The term “alkoxylalkoxy” refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon atom, hydrogen atom and alkoxy groups, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., 2-(methyloxy)ethyloxy, 2-(ethyloxy)ethyloxy, 2-(n-propyloxy)ethyloxy, and 3-(isopropyloxy)butyloxy.

The term “amino acid” refers to a straight or branched hydrocarbon chain containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid and which is attached through the nitrogen atom of the amine group to the rest of the molecule by a single bond, e.g., alanine, valine, isoleucine, leucine, phenylalanine, or tyrosine.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.

The term “aryl” refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The terms “halogen” or “halo” includes fluorine, chlorine, bromine, or iodine.

The terms “heterocyclyl” and “heterocyclic ring” refer to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, tetrazoyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, (1R,5S)-8-azabicyclo[3.2.1]octane. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term “heteroaryl” refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

“Substituted” refers to 1-3 substituents on the same position or on different positions with the same groups or different groups. Unless otherwise specified, the term “substituted” as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted to guanidine, —COOR^(m), —C(O)Rx, —C(S) R^(m), —C(O)NR^(m)R^(y), —C(O)ONR^(m)R^(y), —NR^(m)CONR^(y)R^(z), —N(R^(m))SOR^(y), —N(R^(m))SO₂R^(y), —(═N—N(R^(m))R^(y)), —NR^(m)C(O)OR^(y), —NR^(m)R^(y), —NR^(m)C(O)R^(y), —NR^(m)C(S)R^(y), —NR^(m)C(S)NR^(y)R^(z), —SONR^(m)R^(y), —SO₂NR^(m)R^(y), —OR^(m), —OR^(m)C(O)NR^(y)R^(z), —OR^(m)C(O)OR^(y), —OC(O) R^(m), —OC(O)NR^(m)R^(y), —R^(m)NR^(y)C(O)R^(z), —R^(m)OR^(y), —R^(m)C(O)OR^(y), —R^(m)C(O)NR^(y)R^(z), —R^(m)C(O)R^(y), —R^(m)OC(O)R^(y), —SR^(m), —SOR^(m), —SO₂R^(m), and —ONO₂, wherein R^(m), R^(y) and R^(z) are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned “substituted” groups cannot be further substituted. For example, when the substituent on “substituted alkyl” is “substituted aryl”, the substituent on “substituted aryl” cannot be “substituted alkenyl”.

The term “prodrug” means a compound that is transformed in vivo to yield a compound of Formula (1), (1A) or a pharmaceutically acceptable salt, hydrate or solvate, or metabolite of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term “treating” or “treatment” of a state, disease, disorder or condition includes:

-   -   (1) preventing or delaying the appearance of clinical symptoms         of the state, disease, disorder or condition developing in a         subject that may be afflicted with or predisposed to the state,         disease, disorder or condition but does not yet experience or         display clinical or subclinical symptoms of the state, disease,         disorder or condition;     -   (2) inhibiting the state, disease, disorder or condition, i.e.,         arresting or reducing the development of the state, disease,         disorder or condition or at least one clinical or subclinical         symptom thereof; or     -   (3) relieving the state, disease, disorder or condition, i.e.,         causing regression of the state, disease, disorder or condition         or at least one of its clinical or subclinical symptoms.

The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.

The term “subject” includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

A “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.

The compounds of the present invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of the present invention are capable of existing in stereo isomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the Formula (1), or (1A), the present invention extends to these stereo isomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereo isomeric forms of the present invention may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.

Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

Pharmaceutical Compositions

The pharmaceutical compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.

The subjects contemplated include, for example, a living cell and a mammal, including human. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, or other container.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

The carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick-, sustained-, or delayed-release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy. 20^(th) Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampule, capsule, or sachet. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.

The pharmaceutical compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions, liquids, gels, or products for topical application.

The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is specifically suitable.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Exemplary carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

A typical tablet that may be prepared by conventional tableting techniques.

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

For parenteral application, particularly suitable are injectable solutions or suspensions, specifically aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Methods of Screening

Antiviral HIV activity and cytotoxicity of compounds present invention can be measured in parallel by following the methods published in the literature.

The cytotoxic effect of compounds can be analyzed by measuring the proliferation of cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide (MTT) staining. Cells (5×10³ cells/well) will be incubated in in 96 well plates in the presence or absence of compounds. At the end of treatment, 20 μl of MIT (5 mg/ml in PBS) will be added to each well and incubated for an additional 4 hours at 37° C. The purple-blue MIT formazan precipitate will be dissolved in a triplex reagent containing 10% SDS, 5% isobutanol and 10 mmol/lit HCl. The activity of mitochondria, reflecting cellular growth and viability, will be evaluated by measuring the optical density at 570 nm on micro titer plate.

Action of compounds on replication of HIV in Sup-T1 cells can be determined by the method published by Roda Rani et al., 2006 (Archives of Biochemistry and Biophysics, Volume 456, Issue 1, 1 Dec. 2006, Pages 79-92).

Briefly, 1×10⁶ Sup-T1 cells with 100% cell viability will be seeded in RPMI 1640, 0.1% FBS four 12 well plates. Increasing concentrations of Epap-1 peptides will be added to the cells and will be infected with HIV1_(93 IN 101) each at final concentration of virus equivalent to 2 ng of p24 per ml. The infected cells will be incubated at 37 C and 5% CO2 incubator for 2 hours. After 2 hrs the cells will be pelleted at 350 g for 10 min, supernatant will be discarded and cell will be held with RPMI 1640 containing 10% FBS. The cells will be resuspended in the same medium with increasing concentrations of Epap-1 peptides and will be incubated for 96 hours. The cells will be supplemented with peptides at every 24 hours. The supernatants will be collected after 96 hours and analyzed using P24 antigen capture assay kit (SAIC Fredrick). The infection in the absence of Epap-1 will be considered to be 0% inhibition Azidothymidine (AZT) will be taken as positive control.

Action of compound on virus entry and quantification of virus entered can be done in terms of GFP expression by the following the methods published J. Virol. 72, 6988 (1998) by in Cecilia et al., and Analytical Biochemistry Volume 360, Issue 2, 15 Jan. 2007, Pages 315-317 (Dyavar S. Ravi and Debashis Mitra).

Briefly, cells will be seeded in to wells of 24 well plates 1 day prior to the experiment. The cells will be transfected with Tat-reporter. The virus inoculum will be adjusted to 1,000-4,000 TCID 50/ml in assay medium (DMEM, 10% FCS, glutamine and antibiotics), 50 μl aliquots will be incubated with serial dilutions of compounds (50 μl) for 1 hr at 37° C. The reporter expression will be quantified at appropriate time calculated inhibitory doses referrers to the concentration of these agents in this preincubation mixture.

Other relevant references useful for screening antiviral HTV activity are: Averett, D. R. 1989. Anti-HIV compound assessment by two novel high capacity assays. J. Virol. Methods 23: 263-276; Schwartz, O., et al. 1998; A rapid and simple colorimeric test for the study of anti HIV agents. AIDS Res. and Human Retroviruses, 4(6):441-447; Daluge, S. M., et al. 1994. 5-Chloro-2′,3′-deoxy-3′fluorouridine (935U83), a selective anti human immunodeficiency virus agent with an improved metabolic and toxicological profile; Antimicro. Agents and Chemotherapy, 38(7):1590-1603; H. Mitsuya and S. Border, Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type lymphadenopathy-associated virus (HLTV-III/LAV) by 2,3′-dideoxynucleosides, Proc. Natl. Acad. Sci. USA, 83, 1911-15(1986); Pennington et al., Peptides 1990; Meek T. D et al., Inhibition of HIV-1 protease in infected T-limphocytes by synthetic peptide analogues, Nature, 343, p 90 (1990); Weislow et al., J. Natl. Cancer Inst. 81, 577-586, 1989; T. Mimoto et al., J. Med. Chem., 42, 1789-1802, 1999; Uckun et al 1998, Antimicobial Agents and Chemotherapy 42:383; for P24 antigen assay Erice et al., 1993, Antimicrob. Ag. Chemotherapy 37: 385-383; Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985; Balzarini et al. AIDS (1991), 5, 21-28; Connor t al., Journal of virology, 1996, 70, 5306-5311; Popik et al., Journal of virology, 2002, 76, 4709-4722; Harrigton et al., Journal of Virology Methods, 2000, 88, 111-115; Roos et al., Virology 2000, 273, 307-315; Fedyuk N. V. et al; Problems of Virology 1992, (3)P135; Mosmann T, December 1983, Journal of immunological methods, 65 (1-2), 55-63; SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.

Methods of Treatment

The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections. The connection between therapeutic effect and antiviral is illustrated. For example, PCT publication Nos. WO 011/07646, WO 01/65957, or WO 03/037908; US publication Nos. U.S. Pat. No. 4,598,095 or US 2002/0068757; EP publication Nos. EP 0989862 or EP 0724650; Bioorganic & Medicinal Chemistry Letters, 16, (6), 1712-1715, 2006; and references cited therein, all of which are incorporated herein by reference in their entirety and for the purpose stated.

The present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

Diseases, conditions, and/or disorders that are mediated by viral infections are believed to include, but are not limited to, HIV infection, HBV, HCV, a retroviral infection genetically related to HIV, AIDS, inflammatory disease, respiratory disorders (including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), multiple sclerosis, rheumatoid arthritis, graft rejection (in particular but not limited to kidney and lung allografts), endometriosis, type I diabetes, renal diseases, chronic pancreatitis, inflammatory lung conditions, chronic heart failure and bacterial infections (in particular but not limited to tuberculosis).

Methods of Preparation

The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme-1 to 2. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereoisomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

Compounds of the present invention can be synthesized from naturally occurring Betulinic acid or betulinal. Key intermediates required for synthesizing analogues are either commercially available, or can be prepared by the methods published in the literature.

Compounds of formula 6 (n and R₆ are same as defined above, R₆ is more specifically isopropyl, t-butyl, substituted or unsubstituted phenyl, pyridine, and thiophene) and P can be a protecting group more specifically BOC, benzyl, MOM chloride (chloromethyl methyl ether), tosyl, TBDMS, p-methoxy phenyl (PMP), CBZ chloride, THP, dimethyl acetol, allyl ether, t-butyl ether or phthalimide can be prepared as described in Scheme 1. The acetyl compounds of formula 1 can be converted to bromo compounds of formula 2 in the presence of bromine, N-bromosuccinimide, or the like in the solvents such as THF, diethyl ether, or the like. The bromo compounds of formula 2 can be coupled with BOC protected proline compounds of formula 3 to get the compound of prolinated compounds of formula 4 in the presence of suitable coupling agents such as DIPEA, TEA, potassium carbonate or the like in the solvents such as N,N-Dimethylformamide, dichloromethane, dichloroethane, or the like. The prolinated compounds of formula 4 can be cyclized to proline-cyclic compounds of formula 5 in the presence of ammonium acetate, or the like in the solvents such as toluene, xylene, or the like. The proline-cyclic compounds (BOC protected) of formula 5 can be deprotected to give NH proline compounds of formula 6 in the presence of TFA, HCl or the like in the solvents such as DCM, ethyl acetate or the like.

Compounds of formula 12 [Formula (1), when W=CO] (R₁, R₃, R₄, R₅, R₆, R_(x), R_(c) and n are same as defined above & R_(x) is more specifically substituted or unsubstituted oxadiazole or imidazole or oxazole or triazole and the substituents are more specifically isopropyl, t-butyl, substituted or unsubstituted phenyl, pyridine, and thiophene) can be prepared as described in Scheme 2. Reacting a C-3 alcohol with a suitable ester forming reagents like anhydrides, acid halides or mixed anhydrides in the presence of a base like triethyl amine, diisopropyl ethyl mine, or pyridine in an inert solvent like DCM, toluene, THF or a basic solvent like pyridine with or without addition of a catalyst like DMAP. For example a C-3 alcohol of compounds of the formula 7 can be protected by an acetyl group in the presence of acetic anhydride (as described in T.W. Greene and P.G.M. Wuts, protective groups in organic synthesis, 3^(rd) edition, John Wiley & sons, New York, 1999) in the solvents such as pyridine or the like to give the C-3 acetyl compounds of formula 8. The C-3 acetyl (C-28 acid) compounds of formula 8 can be couple with substituted proline compounds of formula 9 (synthesized as described in Scheme 1) to give the C-28 cyclic amide compounds of formula 10 in the presence of oxylylchloride, TEA or the like in the presence of solvents such as DCM, or the like. The C-28 cyclic amide (C-3 ester) compounds of formula 10 can be hydrolysed to give C-3 hydroxy compounds of formula 11 in the presence of bases such as potassium carbonate, sodium hydroxide, ammonia or the like in the solvents such as methanol:THF, methanol:water, 1,4-dioxane, methanol or the like. The C-3 hydroxy compounds of formula 11 can be reacted with corresponding acid anhydrides, half protected diacids or their mixed anhydrides or acid chlorides to give the corresponding compounds of present invention represented by formula 12 [Formula (1), when W=CO] in the presence a base like triethyl amine, 4-Dimethylaminopyridine, diisopropyl ethyl mine or pyridine or the like in the solvents such as for example, DCM, toluene, EtOAc, THF or the like.

EXPERIMENTAL

The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions.

Intermediates Intermediate 1: Preparation of (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine

Preparation of (tert-butoxycarbonyl)-L-proline

A solution of L-proline (30 g, 260.05 mmol) in 1,4-dioxane (240 mL) stirred at room temperature for about 15 minutes, then added saturated bicarbonate solution (66.4 g, 781.72 mmol, 3 eq). After stirring about 10 minutes at room temperature, di-tert-butyl dicarbonate (69.5 mL, 312.69 mmol) was added. The reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture pH was adjusted to 2 to 3 by addition of 4N hydrochloric acid (Note: the temperature of reaction mixture should be 5-10° C.). The aqueous layer was extracted with dichloromethane, combined organic layer was washed with water, dried over Na₂SO₄, filtered and solvent was evaporated under reduced pressure to afford the desired compound (53 g, yield: 94%) as a white solid.

Step 1: Synthesis of 2-bromo-1-(pyridin-2-yl) ethanone

To the stirred solution of 1-(pyridin-2-yl) ethanone (10 g, 82.6 mmol) in 120 ml of CCl4 at 0° C. was added bromine (4.2 ml, 26.2 mmol) dissolved in CCl4 (20 ml) for about 15 min, and stirred for about 2 hrs at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was, concentrated and the crude product was dissolved in n-hexane and stirred for 30 min. The solid obtained was filtered and washed with n-hexane, dried and proceeded for next step (wt 11.0 g).

Step 2: Synthesis of (S)-1-tert-butyl 2-(2-oxo-2-(pyridin-2-yl)ethyl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (11.9 g, 55.3 mmol) in DCM (120 ml) was added DIPEA (20.3 ml, 158.1 mmol) at 0° C. temperature and after 10 minutes, 2-bromo-1-(pyridin-2-yl) ethanone (step 1, 11.0 g, 54.7 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water followed by saturated brine. The organic layer was concentrated under reduced pressure and the resulting crude was proceeded to next step without further purification (13.0 g)

Step 3: Synthesis of tert-butyl (S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-tert-butyl 2-(2-oxo-2-(pyridin-2-yl)ethyl) pyrrolidine-1,2-dicarboxylate (step 2, 13 g, 38.9 mmol) in toluene (130 ml) was added ammonium acetate (29.9 g, 388.3 mmol) at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc. The organic layer was washed with water, brine and then dried over Na₂SO₄. The solvent was evaporated and the compound was purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (7 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.07-8.52 (m, 2H), 4.98-5.00 (d, 1H, J=6 Hz), 3.52 (s, 2H), 3.01 (s, 1H), 1.98-2.84 (m, 4H), 1.50 (s, 9H); [M+1]⁺ 317 (100%).

Step 4: Synthesis of (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine

A solution with tert-butyl (S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 7 g, 22.2 mmol) in TFA: DCM (1:4, 50 ml) was stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM, TEA (9.6 ml, 101 mmol) and proceeded for next step without further purification (4.5 g).

Intermediate 2: Preparation of(S)-5-(3-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of 2-bromo-1-(3-fluorophenyl)ethan-1-one

To the stirred solution of 3-fluoro Acetophenone (10 g, 71.9 mmol) in 120 ml of MeOH at 0° C. was added bromine (11.5 ml, 71.94 mmol) dissolved in MeOH (20 ml), stirred for about 15 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The solid obtained was filtered, washed with n-hexane, dried and proceeded for next step (wt: 11.0 g).

Step 2: Synthesis of 1-(tert-butyl) 2-(2-(3-fluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (11.9 g, 55.34 mmol) in DCM (120 ml) was added DIPEA (13.0 ml, 0.10 mmol) at 0° C. and after 10 minutes, 2-bromo-1-(3-fluorophenyl)ethan-1-one (step 1, 11.0 g, 51.16 mmol) was added and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water followed by saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was proceeded to next step without further purification (wt: 13.0 g).

Step 3: Synthesis of tert-butyl (S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-(2-(3-fluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate (step 2, 13 g, 36.93 mmol) in toluene (130 ml) was added ammonium acetate (28.43 g, 369.2 mmol) at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc. The organic layer was washed with water, brine and then dried over Na₂SO₄. The solvent was evaporated and the compound was purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 7 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.61-7.63 (m, 2H), 7.17 (s, 1H), 7.10-7.16 (m, 2H), 4.98 (s, 1H), 3.42 (s, 2H), 3.01 (s, 1H), 2.14-2.17 (m, 3H), 1.50 (s, 9H); Mass: 331[M+1]⁺ 332(100%).

Step 4: Synthesis of(S)-5-(3-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 0.89 g, 2.67 mmol) in TFA: DCM (1:4, 50 ml) was stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated and the crude was dissolved in TEA (1.1 ml, 11.45 mmol), DCM and proceeded for next step without further purification (wt: 0.6 g).

Intermediate 3: Preparation of (S)-5-(3-fluoro-4-methylphenyl-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of 2-bromo-1-(3-fluoro-4-methylphenyl)ethan-1-one

To the stirred solution of 3-fluoro-4-methyl Acetophenone (10 g, 65.78 mmol) in 120 ml of MeOH at 0° C. was added bromine (4.2 ml, 26.2 mmol) dissolved in MeOH (20 ml), stirred for about 15 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated, crude product was dissolved in n-hexane and stirred for about 30 minutes. The solid obtained was filtered, washed with n-hexane, dried and proceeded for next step (wt: 11.0 g).

Step 2: Synthesis of 1-(tert-butyl) 2-(2-(3-fluoro-4-methylphenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.8 g, 8.3 mmol) in DCM (20 ml) was added DIPEA (2.9 ml, 22.4 mmol) at 0° C. temperature and after 10 minutes, 2-bromo-1-(3-fluoro-4-methylphenyl)ethan-1-one (step 1, 2.0 g, 8.6 mmol) was added. The reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water followed by saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was proceeded to next step without further purification (wt: 2.6 g).

Step 3: Synthesis of tert-butyl (S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-(2-(3-fluoro-4-methylphenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate (step 2, 2.6 g, 7.1 mmol) in toluene (30 ml) was added ammonium acetate (5.4 g, 70.12 mmol) at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc. The organic layer was washed with water, brine and then dried over Na₂SO₄. The solvent was evaporated and the compound was purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 2 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.61-7.63 (m, 2H), 7.17 (s, 1H), 7.10-7.16 (m, 1H), 4.98 (s, 1H), 3.42 (s, 2H), 3.01 (s, 3H), 2.14-2.17 (m, 3H), 1.50 (s, 9H); Mass: 345[M+1]⁺ 346(100%).

Step 4: Synthesis of (S)-5-(3-fluoro-4-methylphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 0.75 g, 2.1 mmol) in TFA: DCM (1:4, 20 ml) was stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated, the crude was dissolved in DCM and proceeded for next step without further purification (wt: 0.5 g).

Intermediate 4: Preparation of(S)-5-(4-(2-methoxyethoxy)phenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of 1-(4-(benzyloxy)phenyl)ethan-1-one

To a stirred solution of 1-(4-(benzyloxy)phenyl)ethan-1-one (25 g, 183.62 mmol) in DMF (250 ml) were added potassium carbonate (25 g, 181.1 mmol) and benzyl bromide (26.9 ml, 157.3 mmol) at 0° C. and stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated, the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 5% EtOAc in hexane) to afford the title compound (wt: 25 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.08-0.91 (m, 11H), 1.12-1.28 (m, 3H), 1.30-1.33 (m, 10H), 1.50-1.58 (m, 2H), 2.01 (s, 3H), 2.03-2.04 (m, 1H), 7.1-7.2 (m, 2H), 7.3-7.6 (m, 3H); Mass: 226.

Step 2: Synthesis of 1-(4-(benzyloxy)phenyl)-2-bromoethan-1-one

To the stirred solution of 1-(4-(benzyloxy)phenyl)ethan-1-one (step 1, 25 g, 110.5 mmol) in 200 ml of MeOH at 0° C. was added Bromine (4.5 ml, 28.5 mmol) (dropwise addition), stirred for about 30 minutes and stirred for about 4 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The obtained solid was filtered and washed with n-hexane then dried and proceeded for next step (wt: 16.0 g).

Step 3: Synthesis of 2-(2-(4-(benzyloxy)phenyl)-2-oxoethyl) 1-(tert-butyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (15 g, 69.76 mmol) in DCM (160 ml), DIPEA (25 ml, 193.7 mmol) was added at 0° C. temperature and after 10 minutes 1-(4-(benzyloxy)phenyl)-2-bromoethan-1-one (step 2, 22 g, 72.09 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was proceeded to next step without further purification (wt: 32 g).

Step 4: tert-butyl (5)-2-(5-(4-(benzyloxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 2-(2-(4-(benzyloxy)phenyl)-2-oxoethyl) 1-(tert-butyl) (S)-pyrrolidine-1,2-dicarboxylate (step 3, 32 g, 72.89 mmol) in toluene (450 ml), ammonium acetate (56 g, 727.2 mmol) was added at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc, washed with water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 6.0 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.1-7.2 (m, 2H), 7.3-7.6 (m, 3H) 7.61-7.63 (m, 2H), 4.98-5.00 (d, 1H, j=6 Htz), 3.42 (s, 2H), 3.01 (s, 1H), 2.14-2.17 (m, 4H), 1.50 (s, 9H); M. Wt: 419.

Step 5: Synthesis of tert-butyl (S)-2-(S-(4-hydroxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A solution of tert-butyl (S)-2-(5-(4-(benzyloxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 4, 0.5 g, 1.19 mmol) dissolved in EtOAc: MeOH (1:1) and was added 0.25 g of Pd/C (wet: 10%) under N₂ atmosphere and was added (0.3 g, 4.7 mmol) of ammonium formate at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and was washed with hot EtOAc: MeOH (1:1, 50 ml). The filtrate was evaporated under reduced pressure, diluted with water (10 ml), extracted with CH₂Cl₂ (2×200 ml) and brine wash. The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by hexane wash.

Step 6: Synthesis of tert-butyl (S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (S)-2-(5-(4-hydroxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 5, 2 g, 6.0 mmol) in acetonitrile (15 ml) were added Potassium carbonate (1.6 g, 12.12 mmol) and 1-bromo-2-methoxyethane (0.6 ml, 4.7 mmol) at 0° C. and reflux for about 12 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated. The reaction mixture was diluted with ethyl acetate, washed with water, 1N HCl, water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 22% acetone: hexane) to afford the title compound (wt: 1.2 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): 1.50 (m, 9H), 1.94-1.98 (m, 2H), 2.03-2.04 (m, 1H), 2.11-2.13 (m, 1H), 3.01-3.13 (m, 1H), 3.37-3.40 (s, 1H), 3.46 (s, 3H), 3.74-3.76 (m, 2H), 4.12-4.14 (m, 2H), 4.95-4.97 (m, 1H), 6.92-6.94 (d, 2H), 7.10 (s, 1H), 7.54-7.60 (d, 2H), 10.50 (s, 1H); Mass: 388 [M+1]⁺

Step 7: Synthesis of (S)-5-(4-(2-methoxyethoxy)phenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 6, 0.6 g 1.5 mmol) in TFA: DCM (1:2, 15 ml), stirred at 0° C.—room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated and the crude was dissolved in TEA (0.6 ml 5.9 mmol), DCM and proceeded for next step without further purification (0.4 g).

Intermediate 5: Preparation of (S)-3-(2-(pyrrolidin-2-yl-1H-imidazol-5-yl)pyridine

Step 1: Synthesis of 2-bromo-1-(pyridin-3-yl) ethanone

To the stirred solution of 1-(pyridin-3-yl) ethanone (10 g, 82.6 mmol) in 120 ml of diethyl ether at 0° C. was added bromine (4.2 ml, 26.2 mmol) dissolved in diethyl ether (20 ml), stirred for about 15 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated, the crude product was dissolved in n-hexane and stirred for about 30 minutes. The solid obtained was filtered, washed with n-hexane, dried and proceeded for next step (wt: 11.0 g).

Step 2: Synthesis of (S)-1-tert-butyl 2-(2-oxo-2-(pyridin-3-yl)ethyl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (11.9 g, 55.3 mmol) in DCM (120 ml), was added DIPEA (20.3 ml, 158.1 mmol) at 0° C. temperature and after 10 minutes 2-bromo-1-(pyridin-3-yl) ethanone (step 1, 11.0 g, 54.7 mmol) was added and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water followed by saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was proceeded to next step without further purification (wt: 13.0 g).

Step 3: Synthesis of tert-butyl (S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-tert-butyl 2-(2-oxo-2-(pyridin-3-yl)ethyl) pyrrolidine-1,2-dicarboxylate (step 2, 13 g, 38.9 mmol) in toulene (130 ml) was added ammonium acetate (29.9 g, 388.3 mmol) at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc. The organic layer was washed with water, brine and then dried over Na₂SO₄. The solvent was evaporated and the compound was purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 7 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.07-8.52 (m, 2H), 4.98-5.00 (d, 1H, J=6 Hz), 3.52 (s, 2H), 3.01 (s, 1H), 1.98-2.84 (m, 4H), 1.50 (s, 9H). [M+1]⁺ 317 (100%).

Step 4: Synthesis of (S)-3-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine

A solution with tert-butyl (S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 7 g, 22.2 mmol) in TFA: DCM (1:4, 50 ml) was stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated, the crude was dissolved in DCM and TEA (9.6 ml, 95.14 mmol) and proceeded for next step without further purification (wt: 4.5 g).

Intermediate 6: Preparation of (S)-2-(pyrrolidin-2-yl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazole

Step 1: Synthesis of 2-bromo-1-(4-(trifluoromethyl)phenyl ethan-1-one

To the stirred solution of 4-trifluoromethyl Acetophenone (2 g, 10.6 mmol) in 20 ml of MeOH at 0° C. was added bromine (0.43 ml, 2.6 mmol) dissolved in MeOH (20 ml), stirred for about 15 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The solid obtained was filtered and washed with n-hexane, dried and proceeded for next step (wt: 1.7 g).

Step 2: Synthesis of 1-(tert-butyl) 2-(2-oxo-2-(4-(trifluoromethyl) phenyl)ethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.4 g, 1.86 mmol) in DCM (20 ml) was added DIPEA (0.64 ml, 4.96 mmol) at 0° C. After 10 minutes, 2-bromo-1-(4-(trifluoromethyl)phenyl)ethan-1-one (step 1, 0.5 g, 1.86 mmol) was added and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water followed by saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was proceeded to next step without further purification (wt: 0.6 g).

Step 3: Synthesis of tert-butyl (S)-2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of I-(tert-butyl) 2-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) (S)-pyrrolidine-1,2-dicarboxylate (step 2, 0.6 g, 1.49 mmol) in toluene (15 ml) was added ammonium acetate (0.92 g, 11.9 mmol) at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc. The organic layer was washed with water, brine and then dried over Na₂SO₄. The solvent was evaporated and the compound was purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 0.5 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.61-7.63 (m, 2H), 7.17 (s, 1H), 7.10-7.16 (m, 2H), 4.98 (s, 1H), 3.42 (s, 2H), 3.01 (s, 1H), 2.14-2.17 (m, 3H), 1.50 (s, 9H); Mass: 381[M+1]⁺ 382(100%).

Step 4: Synthesis of (S)-2-(pyrrolidin-2-yl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 0.5 g, 1.3 mmol) in TFA: DCM (1:4, 15 ml) was stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and TEA (0.56 ml, 5.60 mmol) proceeded for next step without further purification (wt 0.35 g).

Intermediate 7: Preparation of (S)-5-(4-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of 2-bromo-1-(4-fluorophenyl) ethan-1-one

To the stirred solution of 4-Fluoroacetophenone (10 g, 71.9 mmol) in 120 ml of MeOH at 0° C. was added Bromine (11.5 ml, 71.94 mmol) (dropwise addition), stirred for about 30 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The obtained solid was filtered, washed with n-hexane then dried and proceeded for next step (wt: 11.0 g).

Step 2: Synthesis of 1-(tert-butyl) 2-(2-(4-fluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (11.9 g, 55.34 mmol) in DCM (120 ml), DIPEA (13.0 ml, 0.10 mmol) was added at 0° C. After 10 minutes, 2-bromo-1-(4-fluorophenyl)ethan-1-one (step 1, 11.0 g, 51.16 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude was proceeded to next step without further purification (wt: 13.0 g).

Step 3: tert-butyl (S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-(2-(4-fluorophenyl)-2-oxoethyl)-(S)-pyrrolidine-1,2-dicarboxylate (step 2, 13.0 g, 36.93 mmol) in Toluene (130 ml), ammonium acetate (28.43 g, 369.2 mmol) was added at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated, the crude was diluted with EtOAc, washed with water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt 7.0 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.61-7.63 (m, 2H), 7.17 (s, 1H), 7.10-7.16 (m, 2H), 4.98 (s, 1H), 3.42 (s, 2H), 3.01 (s, 1H), 2.14-2.17 (m, 3H), 1.50 (s, 9H); Mass: 331[M+1]⁺332(100%).

Step 4: Synthesis of (S)-5-(4-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 1.0 g, 3.0 mmol) in TFA: DCM (1:2, 30 ml) and stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated, the crude was dissolved in DCM and proceeded for next step without further purification (wt: 0.8 g).

Intermediate 8: Preparation of(S)-3-phenyl-5-(pyrrolidin-2-yl)-1,2,4-oxadiazole

Step 1: Synthesis of (Z)—N′-hydroxybenzimidamide

To the stirred solution of benzonitrile (12.0 g, 116.5 mmol) in 100 ml of methanol at room temperature was added K₂CO₃ (24.1 g, 174.6 mmol), stirred for about 10 minutes, then added hydroxylamine hydrochloride (16 g, 231.8 mmol) (dissolved in 120 ml of methanol) and stirred for about 10 minutes at room temperature and refluxed for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered, concentrated, the crude product was dissolved 1N EtOAc, washed with water, brine and dried over Na₂SO₄. The solvent was evaporated and used without further purification (wt 10.0 g).

Step 2: Synthesis of (S,Z)-tert-butyl 2-((amino(phenyl)methyleneaminooxy)carbonyl) pyrrolidine-1-carbaxylate

To a stirred solution of Boc-proline (15.8 g, 73.05 mmol) in DCM (200 ml), EDCI (21.05 g, 109.5 mmol) and HOBt (13.4 g, 88.1 mmol) were added at room temperature. After 10 minutes, (Z)—N′-hydroxybenzimidamide (step 1, 10.0 g, 73.05 mmol) was added and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated with brine and the organic layer was concentrated under reduced pressure. The resulting crude was proceeded to next step without further purification (wt: 18.0 g).

Step 3: Synthesis of (S)-tert-butyl 2-(3-phenyl-1,2, 4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S,Z)-tert-butyl 2-((amino(phenyl)methyleneaminooxy) carbonyl)pyrrolidine-1-carboxylate (step 2, 18.0 g, 54.05 mmol) in pyridine (80 ml) at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water, 1N HCl, water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 13.0 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.06-8.08 (m, 2H), 7.47-7.50 (m, 2H), 5.05-5.22 (m, 1H), 3.48-3.62 (m, 2H), 2.07-2.43 (m, 3H), 1.95 (s, 9H); Mass: 315. [M+Na]⁺ 338 (100%).

Step 4: Synthesis of (S)-3-phenyl-5-(pyrrolidin-2-yl)-1,2,4-oxadiazole

A solution of (S)-tert-butyl 2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate (step 3, 12.0 g, 38.21 mmol) in TFA: DCM (1:2, 3 ml) and stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated, the crude was dissolved in DCM and proceeded for next step without further purification.

Intermediate 9: Preparation of 2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-4-phenyl-1H-imidazole

Step 1: Synthesis of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

To a stirred solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (50.0 g, 381.3 mmol) in 1,4-dioxane (250 ml) at 0° C. was added aqueous NaHCO₃ (96.10 g dissolved in 500 ml H₂O, 1144 mmol). After stirring 10 minutes at 0° C., the reaction mixture was treated with di-tert-butyl dicarbonate (99.86 g, 457.5 mmol) and the resulting solution was stirred at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice cold water, the solution pH was adjusted to 2 to 3 by addition of 4N HCl (Note: the temperature of reaction mixture should be 5-10° C.). The aqueous layer was extracted with ethyl acetate (2×500 ml), combined organic layer was washed with brine, dried over Na₂SO₄, filtered and solvent was evaporated under reduced pressure to provide title compound (wt: 85.0 g, yield: 96%).

Step 2: Synthesis of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy)pyrrolidine-2-carboxylic acid

A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (step 1, 20.0 g, 86.9 mmol) in DMF (200 ml) was treated with sodium hydride (8.43 g, 347.8 mmol) at 0° C. After stirring about 15 minutes at 0° C., 1-bromo-2-methoxyethane (24.2 g, 174.0 mmol) was added and stirred at ambient temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C., then 400 ml water was added slowly over 30 minutes and stirred at room temperature for about 4 hours. Ethyl acetate (200 ml) was added to the reaction mixture and two layers were separated. The aqueous phase was acidified (pH˜5) with 6N HCl, extracted with ethyl acetate (2×300 ml), washed with brine, dried over Na₂SO₄ and concentrated to afford title compound (wt: 14.50 g, yield: 58%). H¹ NMR (DMSO-D₆, 300 MHz): δ 12.58 (bs, 1H), 4.05 (m, 2H), 3.50 (m, 2H), 3.41 (m, 4H), 3.23 (s, 1H), 2.26 (m, 1H), 1.97 (m, 1H), 1.39 & 1.34 (2s, 9H).

Step 3: Synthesis of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-(2-methoxyethoxy) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy) pyrrolidine-2-carboxylic acid (step 2, 3.20 g, 11.07 mmol) in DCM (50 ml) at 0° C. was added DIPEA (3.80 ml, 22.14 mmol). After stirring about 10 minutes, 2-bromo-1-phenylethanone (2.20 g, 11.07 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with dichloromethane (200 ml), washed with water (200 ml), saturated brine (100 ml) and the organic layer was concentrated under reduced pressure to afford title compound (wt: 4.5 g). The crude product was used in the next step without further purification. H¹ NMR (DMSO-D₆, 300 MHz): δ 7.96 (d, J=8.0 Hz, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 2H), 5.56 (s, 2H), 4.35 (m, 1H), 4.15 (m, 1H), 3.57 (m, 2H), 3.44 (m, 4H), 3.23 (s, 3H), 2.41 (m, 1H), 2.26 (m, 1H), 1.36 & 1.25 (2s, 9H).

Step 4: Synthesis of (2S,4R)-tert-butyl 4-(2-methoxyethoxy)-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl)4-(2-methoxyethoxy) pyrrolidine-1,2-dicarboxylate (step 3, 4.5 g, 11.05 mmol) in toluene (50 ml), ammonium acetate (8.52 g, 110.56 mmol) was added at room temperature and resulting reaction mixture was refluxed for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added, extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2×100 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×100 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (wt: 4.0 g, yield: 93%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.91 (bs, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.31 (t, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 4.75 (m, 1H), 4.18 (m, 1H), 3.4-3.60 (m, 6H), 3.26 (s, 3H), 2.34 (m, 1H), 2.08 (m, 1H), 1.38 & 1.20 (2s, 9H).

Step 5: Synthesis of 2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-4-phenyl-1H-imidazole

To a solution of (2S,4R)-tert-butyl 4-(2-methoxyethoxy)-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (step 4, 4.0 g, 10.36 mmol) in DCM (40 ml) was added trifluoroacetic acid (10 ml) and stirred at room temperature for about 4 hours. After completion of the reaction, solvents were evaporated and aqueous sodium bicarbonate was added to the residue. The product was extracted with dichloromethane (2×100 ml), washed with brine, dried over Na₂SO₄ and filtered. The solvents were evaporated under reduced pressure to afford title compound (wt: 2.1 g, yield: 69%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.86 (bs, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.44 (s, 1H), 7.31 (t, J=8.0 Hz, 2H), 7.30 (m, 1H), 7.15 (t, J=8.0 Hz, 1H), 4.28 (t, J=8.6 Hz, 1H), 4.10 (m, 1H), 3.4-3.60 (m, 4H), 3.26 (s, 3H), 3.13 (m, 1H), 2.87 (m, 1H) & 2.15 (m, 2H).

Intermediate 10; Preparation of 4-(3-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy) pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate

Step 1: Synthesis of (2S,4R)-1-tert-butyl 2-(2-(3-fluorophenyl)-2-oxoethyl) 4-(2-methoxy ethoxy)pyrrolidine-1,2-dicarboxylate

To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy) pyrrolidine-2-carboxylic acid (Example 20-step 2, 10.0 g, 34.72 mmol) in DCM (100 ml) at 0° C. was added DIPEA (13.46 g, 104.36 mmol) and after stirring about 10 minutes, 2-bromo-1-(3-fluorophenyl)ethanone (7.53 g, 34.72 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. Water was added to the reaction mixture and extracted with dichloromethane (2×250 ml) and washed with brine solution. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (wt: 14.7 g, yield: 100%). The crude product was used in the next step without further purification. H^(L) NMR (DMSO-D₆, 300 MHz): δ 7.82 (m, 2H), 7.60 (m, 2H), 5.60 (m, 2H), 4.32 (m, 1H), 4.15 (m, 1H), 3.3-3.61 (m, 6H), 3.23 (s, 3H), 2.41 (m, 1H), 2.26 (m, 1H), 1.36 & 1.25 (2s, 9H).

Step 2: Synthesis of (2S,4R)-tert-butyl 2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxy ethoxy)pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-(3-fluorophenyl)-2-oxoethyl) 4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxylate (step 1, 5.0 g, 11.76 mmol) in toluene (50 ml), ammonium acetate (18.11 g, 235.29 mmol) was added at room temperature and resulting mixture was refluxed for about 18 hours. The reaction mixture was cooled to room temperature, added water and extracted with ethyl acetate (2×250 ml) and the organic layer was washed with 1N HCl (2×100 ml). Aqueous layer was basified (pH˜8 to 9) with 2N NaOH, the product was extracted with ethyl acetate (2×200 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (wt: 2.56 g, yield: 54%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.04 (bs, 1H), 7.48-7.70 (m, 3H), 7.35 (m, 1H), 6.93 (m, 1H), 4.75 (m, 1H), 4.18 (m, 1H), 3.43-3.60 (m, 6H), 3.26 (s, 3H), 2.34 (m, 1H), 2.08 (m, 1H), 1.38 & 1.20 (2s, 9H).

Step 3: Synthesis of 4-(3-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-Imidazole 2, 2,2-trifluoroacetate

To a solution of ((2S,4R)-tert-butyl 2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate (step 2, 2.50 g, 6.17 mmol) in DCM (30 ml) was added trifluoroacetic acid (12 ml) and stirred at room temperature for about 3 hours. After completion of the reaction, the solvents were evaporated under reduced pressure to afford title compound (wt: 2.58 g, yield: 100%). H¹ NMR (DMSO-D₆, 300 MHz): δ 9.90 (bs, 1H), 9.19 (bs, 1H), 7.82 (s, 1H), 7.61 (m, 2H), 7.41 (s, 1H), 7.08 (m, 1H), 4.81 (m, 1H), 4.41 (m, 1H), 3.3-3.60 (m, 6H), 3.27 (s, 3H), 2.3-2.60 (m, 2H).

Intermediate 11: Preparation of 4-(4-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy) pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate

Step 1: Synthesis of (2S,4R)-1-tert-butyl 2-(2-(4-fluorophenyl)-2-oxoethyl) 4-(2-methoxy ethoxy)pyrrolidine-1,2-dicarboxylate

To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy) pyrrolidine-2-carboxylic acid (Example 20-step 2, 3.2 g, 11.07 mmol) in DCM (50 ml) at 0° C. was added DIPEA (3.8 ml, 22.14 mmol) and after stirring about 10 minutes at 0° C., 2-bromo-1-(4-fluorophenyl)ethanone (2.4 g, 11.07 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. The reaction mixture was diluted with water, extracted with dichloromethane (200 ml) and washed with brine solution (100 ml), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified on silica gel column (100-200 mesh, eluted with 30% ethyl acetate/hexanes) to afford the title compound (4.5 g, 96%). H¹ NMR (DMSO-D₆, 300 MHz): δ 8.06 (m, 2H), 7.40 (m, 2H), 5.56 (m, 2H), 4.32 (m, 1H), 4.14 (m, 1H), 3.55 (m, 2H), 3.44 (m, 4H), 3.25 (s, 3H), 2.40 (m, 1H), 2.24 (m, 1H), 1.36 & 1.39 (2s, 9H).

Step 2: Synthesis of (2S,4R)-tert-butyl 2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxy ethoxy)pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-(4-fluorophenyl)-2-oxoethyl) 4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxylate (step 1, 4.5 g, 10.58 mmol) in toluene (60 ml), ammonium acetate (8.15 g, 105.8 mmol) was added at room temperature and refluxed for about 18 hours. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2×200 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×200 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (3.2 g, 75%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.94 (bs, 1H), 7.75 (m, 2H), 7.48 (s, 1H), 7.13 (m, 2H), 4.75 (m, 1H), 4.18 (m, 1H), 3.4-3.70 (m, 6H), 3.26 (s, 3H), 2.34 (m, 1H), 2.08 (m, 1H), 1.38 & 1.11 (2s, 9H).

Step 3: Synthesis of 4-(4-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate

To a solution of (2S,4R)-tert-butyl 2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate (step 2, 3.2 g, 7.90 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (15 ml) and stirred at room temperature for about 3 hours. After completion of the reaction and the solvents were evaporated under reduced pressure to afford title compound (3.3 g, 100%). H¹ NMR (DMSO-D₆, 300 MHz): δ 12.15 (bs, 1H), 7.77 (m, 3H), 7.53 (s, 1H), 7.17 (m, 2H), 4.50 (m, 1H), 4.23 (m, 1H), 3.4-3.70 (m, 5H), 3.26 (s, 3H), 3.05 (m, 1H), 2.27 (m, 1H), 2.15 (m, 1H); Mass (ESI): 306.13 (M+H).

Intermediate 12: Preparation of 3-(2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine 2,2,2-trifluoroacetate

Step 1: Synthesis of (2S,4R)-1-tert-butyl 2-(2-oxo-2-(pyridin-3-yl)ethyl) 4-(2-methoxyethoxy) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy) pyrrolidine-2-carboxylic acid (Example 20-step 2, 20.0 g, 69.44 mmol) in DCM (200 ml) at 0° C. was added triethyl amine (29 ml, 208.3 mmol) at 0° C. and after stirring about 10 minutes at 0° C., 2-bromo-1-(pyridin-3-yl)ethanone (21.46 g, 76.38 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. Water was added to the to reaction mixture, extracted with dichloromethane (2×200 ml) and washed with brine solution (100 ml), dried over Na₂SO₄, and filtered. The solvent was concentrated under reduced pressure to afford title compound (16.0 g, 56%). The crude product was used in the next step without further purification. H¹ NMR (DMSO-D₆, 300 MHz): δ 9.14 (s, 1H), 8.85 (d, J=4.0 Hz, 1H), 8.32 (dd, J=8.6, 2.0 Hz, 1H), 7.60 (dd, J=8.6, 4.0 Hz, 1H), 5.60 (m, 2H), 4.35 (m, 1H), 4.15 (m, 1H), 3.57 (m, 2H), 3.44 (m, 3H), 3.25 (s, 3H), 3.10 (m, 1H), 2.41 (m, 1H), 2.26 (m, 1H), 1.40 & 1.36 (2s, 9H).

Step 2: Synthesis of (2S,4R)-tert-butyl 4-(2-methoxyethoxy)-2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-oxo-2-(pyridin-3-yl)ethyl) 4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxylate (step 1, 16.0 g, 39.21 mmol) in toluene (100 ml), ammonium acetate (24.15 g, 313.72 mmol) was added at room temperature and refluxed for about 24 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2×150 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×100 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (8.2 g, 54%). H¹ NMR (DMSO-D₆, 300 MHz): δ 12.10 (bs, 1H), 8.94 (s, 1H), 8.35 (d, J=4.3 Hz, 1H), 8.06 (dd, J=8.6, 2.0 Hz, 1H), 7.35 (s, 1H), 7.60 (dd, J=8.6, 4.3 Hz, 1H), 4.79 (m, 1H), 4.17 (m, 1H), 3.43-3.59 (m, 6H), 3.26 (s, 3H), 3.10 (m, 1H), 2.35 (m, 1H), 2.08 (m, 1H), 1.38 & 1.11 (2s, 9H).

Step 3: Synthesis of 3-(2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine 2,2,2-trifluoroacetate

To a solution of (2S,4R)-tert-butyl (2S,4R)-tert-butyl 4-(2-methoxyethoxy)-2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 1.20 g, 3.09 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (15 ml) and stirred at room temperature for about 3 hours. After completion of the reaction, the solvents were evaporated under reduced pressure to afford title compound (1.0 g, 81%). H¹ NMR (DMSO-D₆, 300 MHz): δ 10.08 (bs, 1H), 9.32 (bs, 1H), 9.19 (s, 1H), 8.74 (m, 1H), 8.12 (s, 1H), 7.96 (m, 1H), 4.87 (m, 1H), 4.43 (m, 1H), 3.43-3.59 (m, 6H), 3.26 (s, 3H), 2.58 (m, 1H), 2.35 (m, 1H); Mass (ESI): 289.23 (M+H).

Intermediate 13: Preparation of (S)-2-Phenyl-5-(pyrrolidin-2-yl)-1,3,4-oxadiazole

Step 1: Synthesis of (S)-Benzyl 2-(hydrazinocarbonyl)pyrrolidine-1-carboxylate

A mixture of (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (5.0 g, 20.08 mmol), triethyl amine (5.60 ml g, 40.16 mmol) and HATU (9.16 g, 24.09 mmol) in dichloromethane (50 ml) was stirred for about 15 minutes then added hydrazine hydrate (1.50 g, 30.12 mmol) and allowed to stir at room temperature for about 18 hours. The mixture was diluted with dichloromethane (200 ml), successively washed with water, aq. NaHCO₃ solution and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (100-200 mesh) using 5% methanol/dichloromethane to afford the title compound (4.20 g, 80%). H¹ NMR (DMSO-D₆, 300 MHz): δ 9.15 (d, 1H), 7.28-7.38 (m, 5H), 5.05 (s, 2H), 4.15 (m, 3H), 3.44 (m, 2H), 1.7-2.20 (m, 4H).

Step 2: Synthesis of (S)-Benzyl 2-(2-benzoylhydrazinecarbonyl)pyrrolidine-1-carboxylate

To a mixture of (S)-benzyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (step 1, 2.20 g, 8.36 mmol), benzoic acid (1.50 g, 12.29 mmol) and HATU (4.7 g, 12.36 mmol) in dichloromethane (40 ml) was added diisopropylethyl amine (2.1 g, 32.55 mmol) and stirred at room temperature for about 3 hours. The mixture was diluted with dichloromethane (100 ml), successively washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (100-200 mesh) to afford the title compound (1.10 g, 36%). H¹ NMR (DMSO-D₆, 300 MHz): δ 10.42 (bs, 1H), 10.04 (bs, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.59 (m, 3H), 7.35 (m, 5H), 5.08 (s, 2H), 4.35 (m, 1H), 3.4-3.60 (m, 2H), 1.8-2.5 (m, 4H).

Step 3: Synthesis of(S)-Benzyl 2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-benzyl 2-(2-benzoylhydrazinecarbonyl)pyrrolidine-1-carboxylate (step 2, 1.0 g, 2.72 mmol), tosyl chloride (2.06 g, 10.90 mmol) and diisopropylethyl amine (1.75 g, 13.62 mmol) in dichloromethane (30 ml) was stirred at room temperature for about 18 hours. The mixture was diluted with dichloromethane (100 ml), successively washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (100-200 mesh) using 20-25% ethyl acetate/hexanes as eluent to afford title compound (480 mg, 50%). H¹ NMR (DMSO-D₆, 300 MHz): δ 7.97 (d, J=7.5 Hz, 2H), 7.59 (m, 3H), 7.35 (m, 3H), 7.12 (m, 2H), 5.22 (m, 1H), 5.10 (s, 2H), 3.4-3.70 (m, 2H), 1.9-2.5 (m, 4H).

Step 4: Synthesis of (S)-2-Phenyl-5-(pyrrolidin-2-yl)-1,3,4-oxadiazole

To a stirred solution of (S)-benzyl 2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carboxylate (step 3, 1.50 g, 4.31 mmol), ammonium formate (1.35 g, 21.55 mmol) in ethanol (30 ml) was added 10% Pd/C (300 mg) and the resulting mixture was refluxed for about 3 hours. Cooled to room temperature, the catalyst was filtered and solvent was evaporated to afford the title compound (550 mg, 59%). The crude compound was used for the next reaction without further purification. H¹ NMR (DMSO-D₆, 300 MHz): δ 7.97 (d, J=7.5 Hz, 2H), 7.59 (m, 3H), 5.22 (m, 1H), 3.4-3.70 (m, 2H), 1.9-2.5 (m, 4H).

Intermediate 14: Preparation of(S)-4-tert-butyl-2-(pyrrolidin-2-yl)oxazole

Step 1: Synthesis of (S)-1-tert-butyl 2-(3,3-dimethyl-2-oxobutyl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.0 g, 9.30 mmol) in DCM (40 ml) was added DIPEA (2.40 g, 18.60 mmol) at 0° C. and after stirring about 10 minutes, 1-bromo pinacalone (1.83 g, 10.23 mmol) was added and the reaction mixture was stirred at room temperature for about 12 hours. The reaction was diluted with dichloromethane (75 ml) and washed with water (100 ml), saturated brine (100 ml) and the organic layer was concentrated under reduced pressure to afford the title compound (2.50 g). The crude product was used in the next step without further purification.

Step 2: Synthesis of (S)-tert-butyl 2-(4-tert-butyloxazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-tert-butyl 2-(3,3-dimethyl-2-oxobutyl) pyrrolidine-1,2-dicarboxylate (step 1, 2.50 g, 7.98 mmol) in toluene (30 ml) was added ammonium acetate (5.53 g, 71.88 mmol) at room temperature and refluxed for about 18 hours. Cooled to room temperature, diluted with ethyl acetate (150 ml) and the organic layer was washed with water, brine (100 ml), dried over Na₂SO₄, filtered and the organic layer was concentrated under reduced pressure to afford the title compound (1.2 g, 44% over 2 steps). H¹ NMR (DMSO-D₆, 300 MHz): δ 7.22 (s, 1H), 4.87 (m, 1H), 3.4-3.70 (m, 2H), 2.30 (m, 1H), 2.05 (m, 2H), 1.88 (m, 1H), 1.27 & 1.29 (2s, 18H).

Step 3: Synthesis of (S)-4-tert-butyl-2-(pyrrolidin-2-yl)oxazole

To a solution of (S)-tert-butyl 2-(4-tert-butyloxazol-2-yl)pyrrolidine-1-carboxylate (step 2, 1.20 g, 4.09 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (2 ml) and stirred at room temperature for about 4 hours. After completion of the reaction, diluted with water and washed with ethyl acetate (2×75 ml). The aqueous layer was basified with aq. NaHCO₃ solution, extracted with dichloromethane (2×100 ml), washed with brine, dried over Na₂SO₄ and filtered. The solvents were evaporated under reduced pressure to afford title compound (620 mg, 78%). H¹ NMR (DMSO-D₆, 300 MHz): δ 7.62 (s, 1H), 4.17 (m, 1H), 2.85 (m, 2H), 2.0 (m, 1H), 1.6-1.92 (m, 3H), 1.18 (s, 9H).

Intermediate 15: Preparation of(S)-5-methyl-4-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of (2S)-1-tert-butyl 2-(1-oxo-1-phenylpropan-2-yl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2.0 g, 9.30 mmol) in DCM (40 ml) at 0° C. was added DIPEA (3.20 ml, 18.60 mmol) and after stirring about 10 minutes, 2-bromo-1-phenylpropan-1-one (1.98 g, 9.30 mmol) was added and the reaction mixture was stirred at room temperature for about 18 hours. The reaction mixture was diluted with dichloromethane (200 ml), washed with water (200 ml), saturated brine, dried over Na₂SO₄, filtered and the organic layer was concentrated under reduced pressure to afford the title compound (3.10 g, 96%). The crude product was used in the next step without further purification. H¹ NMR (CDCl₃, 300 MHz): δ 7.93 (d, J=10.0 Hz, 2H), 7.58 (m, 1H), 7.33 (m, 2H), 6.05 (m, 1H), 4.35 (m, 1H), 3.48 (m, 2H), 2.0-2.25 (m, 2H), 1.88 (m, 2H), 1.56 (d, 3H), 1.51 (s, 9H).

Step 2: Synthesis of (S)-tert-butyl 2-(5-methyl-4-phenyl-H-imidazol-2-yl)pyrrolidine-J-carboxylate

To a stirred solution of (2S)-1-tert-butyl 2-(1-oxo-1-phenylpropan-2-yl) pyrrolidine-1,2-dicarboxylate (step 1, 3.10 g, 8.93 mmol) in toluene (30 ml), ammonium acetate (6.88 g, 89.33 mmol) was added at room temperature and refluxed for about 16 hours. Cooled to room temperature, the reaction mixture was diluted with ethyl acetate (200 ml) and the organic layer was washed with 1 N HCl (2×100 ml). Aqueous layer was basified (pH=8-9) with 2N NaOH, extracted with dichloromethane (2×100 ml), dried over Na₂SO₄, filtered and concentrated to afford title compound (1.23 g, 42%). H¹ NMR (DMSO-D, 300 MHz): δ 11.61 (bs, 1H), 7.61 (d, J=10.0 Hz, 2H), 7.33 (t, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.51 (m, 1H), 3.36 (m, 1H), 2.35 (s, 3H), 2.0-2.25 (m, 2H), 1.88 (m, 2H), 1.34 & 1.16 (2s, 9H).

Step 3: Synthesis of (S)—5-methyl-4-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole

To a solution of (S)-tert-butyl 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 1.20 g, 3.66 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (5 ml) and stirred at room temperature for about 4 hours. Reaction mixture was concentrated, aqueous sodium bicarbonate solution was added to the residue and extracted with dichloromethane (2×100 ml), washed with brine, dried over Na₂SO₄ and filtered. The solvents were evaporated under reduced pressure to afford title compound (660 mg, 79%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.67 (bs, 1H), 7.70 (m, 1H), 7.58 (d, J=10.0 Hz, 2H), 7.35 (t, J=8.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 4.16 (m, 1H), 3.0 (m, 1H), 2.85 (m, 1H), 2.33 (s, 3H), 2.05 (m, 1H), 1.88 (m, 1H), 1.75 (m, 2H); Mass (ESI): 228.06 [M+H]⁺.

Intermediate 16: Preparation of (S)-4-isopropyl-2-(pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate

Step 1: Synthesis of (S)-tert-butyl 2-(3-methyl-2-oxobutylcarbamoyl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (10.0 g, 46.51 mmol) in DMF (80 ml) at 0° C. was added DIPEA (32.0 ml, 186.0 mmol) and HATU (23.6 g, 60.46 mmol). After stirring 20 minutes, 1-amino-3-methylbutan-2-one hydrochloride (5.06 g, 37.2 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate (2×250 ml) and washed with water (200 ml), saturated brine (100 ml) and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, 30-40% ethyl acetate in hexanes) to afford the title compound (8.10 g, 58%). H¹ NMR (DMSO-d6, 300 MHz): δ 8.02 (broad t, 1H), 4.14 (m, 1H), 3.95 (m, 2H), 3.25-3.50 (m, 2H), 2.72 (m, 1H), 2.10 (m, 1H), 1.75-1.90 (m, 3H), 1.33 & 1.39 (2s, 9H), 1.01 (d, J=8.0 Hz, 6H).

Step 2: Synthesis of (S)-tert-butyl 2-(4-isopropyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-tert-butyl 2-(3-methyl-2-oxobutylcarbamoyl) pyrrolidine-1-carboxylate (step 1, 6.0 g, 20.13 mmol) in xylene (100 ml), ammonium acetate (17.0 g, 221.0 mmol) was added at room temperature and heated at 140° C. for about 48 hours. The reaction mixture was cooled to room temperature, the pH was adjusted (pH˜7-8) with aq. NaHCO₃ solution and extracted with ethyl acetate (2×300 ml). The organic layer was washed with 1 N HCl (2×200 ml) and then the aqueous layer was basified with 2N NaOH (200 ml), product was extracted with ethyl acetate (2×300 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford the title compound (1.50 g, 26%) as a solid. H¹ NMR (DMSO-d6, 300 MHz): δ 11.40 (broad peak, 1H), 6.53 (broad s, 1H), 4.65 (m, 1H), 3.45 (m, 2H), 2.73 (m, 1H), 2.10 (m, 1H), 1.75-1.90 (m, 3H), 1.33 & 1.39 (2s, 9H), 1.18 (d, J=8.0 Hz, 6H); Mass (ESI): 280.11 [M+H]⁺.

Step 3: Synthesis of (S)-4-isopropyl-2-(pyrrolidin-2-yl)-1H-imidazole 2, 2,2-trifluoroacetate

To a solution of (S)-tert-butyl 2-(4-isopropyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 1.0 g, 3.58 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (5 ml) and stirred at room temperature for about 4 hours. After completion of the reaction, the solvents were evaporated under reduced pressure to afford title compound (798 mg, 76%). H¹ NMR (DMSO-D₆, 300 MHz): δ 9.87 (br peak, 2H), 7.03 (s, 1H), 5.09 (m, 1H), 3.65 (m, 1H), 3.50 (m, 1H), 3.05 (m, 1H), 2.0-2.40 (m, 4H), 1.32 (d, J=7.5 Hz, 6H).

Intermediate 17: Preparation of (S)-5-phenyl-2-(pyrrolidin-2-yl)oxazole

Step 1: Synthesis of (S)-benzyl 2-(2-oxo-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (10.2 g, 40.8 mmol) in DCM (100 ml) at 0° C. was added DIPEA (13.8 ml, 81.8 mmol) and EDC (13.80 g, 61.4 mmol). After stirring 20 minutes, 2-amino-1-phenylethanone hydrochloride (7.0 g, 40.93 mmol) was added and the reaction mixture was stirred at room temperature for about 18 hours. The reaction mixture was diluted with water, extracted with dichloromethane (2×150 ml) and organic layer was washed aq. NaHCO₃, brine and dried over Na₂SO₄. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel 100-200 mesh, 50% ethyl acetate in hexanes) to afford title compound (9.4 g, 63%). H¹ NMR (DMSO-d6, 300 MHz): δ 8.30 (broad peak, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.67 (t, J=8.3 Hz, 1H), 7.54 (t, J=8.3 Hz, 2H), 7.32 (m, 5H), 5.04 (m, 2H), 4.56 (m, 2H), 4.32 (m, 1H), 3.30-3.50 (m, 2H), 2.15 (m, 1H), 1.75-1.95 (m, 3H).

Step 2: Synthesis of (S)-benzyl 2-(5-phenyloxazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-benzyl 2-(2-oxo-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate (step 1, 1.0 g, 2.73 mmol) in acetonitrile (10 ml) at 0° C. was added POCl₃ (2.5 ml, 27.32 mmol) and the resulting solution was heated at 90° C. for about 3 hours. The reaction mixture was cooled to room temperature, quenched with ice water and extracted with ethyl acetate (2×50 ml). The organic layer was washed with aq. NaHCO₃ solution, brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using 20% ethyl acetate/hexanes as eluent to afford the title compound (800 mg, 84%). H¹ NMR (DMSO-d6, 300 MHz): δ 7.64 (d, J=8.3 Hz, 2H), 7.58 (s, 1H), 7.45 (t, J=8.3 Hz, 2H), 7.35 (m, 3H), 7.12 (m, 3H), 4.9-5.10 (m, 3H), 3.40-3.70 (m, 2H), 2.30 (m, 1H), 1.9-2.10 (m, 3H); Mass (ESI): 349.06 [M+H]⁺.

Step 3: Synthesis of (S)-5-phenyl-2-(pyrrolidin-2-yl)oxazole

A solution of (S)-benzyl 2-(5-phenyloxazol-2-yl)pyrrolidine-1-carboxylate (step 2, 800 mg, 2.29 mmol) in EtOH (10 ml) was added 10% Pd/C (170 mg) and stirred at room temperature under balloon pressure for about 18 hours. The catalyst was filtered through Celite bed and the filtrate was concentrated to afford the title compound (430 mg, 87%). H¹ NMR (DMSO-D₆, 300 MHz): δ 10.10 (broad peak, 1H), 7.75 (m, 3H), 7.48 (m, 2H), 7.41 (m, 1H), 4.93 (t, J=8.3 Hz, 1H), 3.32 (t, J=8.3 Hz, 2H), 2.25-2.50 (m, 2H), 1.95-2.15 (m, 2H).

Intermediate 18: Preparation of (S)-tert-butyl-2-(pyrrolidin-2-yl)oxazole

Step 1: Synthesis of (S)-benzyl 2-(3,3-dimethyl-2-oxobutylcarbamoyl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (4.0 g, 16.0 mmol) in DMF (50 ml) at 0° C. was added DIPEA (10.8 ml, 64.0 mmol) and HATU (8.13 g, 20.8 mmol). After stirring 20 minutes, 1-amino-3,3-dimethylbutan-2-one hydrochloride (2.39 g, 12.8 mmol) was added and the reaction mixture was stirred at room temperature for about 18 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (2×1000 ml) and washed with water, saturated brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford title compound (1.6 g, 30%). H¹ NMR (DMSO-d6, 300 MHz): δ 8.0 (broad peak, 1H), 7.32 (m, 5H), 5.05 (m, 2H), 4.27 (m, 1H), 4.10 (m, 2H), 3.45 (m, 2H), 2.10 (m, 1H), 1.75-1.90 (m, 3H), 1.11 (s, 9H).

Step 2: Synthesis of (S)-benzyl 2-(5-tert-butyloxazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-benzyl 2-(3,3-dimethyl-2-oxobutylcarbamoyl)pyrrolidine-1-carboxylate (step 1, 1.6 g, 4.62 mmol) in acetonitrile (30 ml) at 0° C. was added POCl₃ (7.0 g, 46.24 mmol) and resulting solution was heated at 90° C. for about 3 hours. The reaction mixture was cooled to room temperature, quenched with ice water and extracted with ethyl acetate (2×100 ml). The organic layer was washed with aq. NaHCO₃ solution, brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography using 25% ethyl acetate/hexanes as eluent to afford the title compound (700 mg, 46%). H¹ NMR (DMSO-d6, 300 MHz): δ 7.32 (m, 4H), 7.08 (m, 1H), 6.71 (s, 1H), 4.85-5.07 (m, 3H), 3.51 (m, 2H), 2.21 (m, 1H), 1.90 (m, 3H), 1.21 & 1.16 (2s, 9H).

Step 3: Synthesis of (S)-5-tert-butyl-2-(pyrrolidin-2-yl)oxazole

A solution of (S)-benzyl 2-(5-tert-butyloxazol-2-yl)pyrrolidine-1-carboxylate (step 2, 700 mg, 2.13 mmol) in EtOH (15 ml) was added 10% Pd/C (150 mg) and stirred at room temperature under balloon pressure for about 18 hours. The catalyst was filtered through Celite bed and the filtrate was concentrated to afford the title compound (380 mg, 92%). H¹ NMR (DMSO-D₆, 300 MHz): δ 6.67 (s, 1H), 4.16 (m, 1H), 2.85 (m, 2H), 1.60-2.06 (m, 4H), 1.21 (s, 9H).

Intermediate 19: Preparation of (S)-4-phenyl-2-(pyrrolidin-2-yl)oxazole

Step 1: Synthesis of (S)-1-benzyl 2-(2-oxo-2-phenylethyl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (10.0 g, 40.16 mmol) in DCM (100 ml) at 0° C. was added triethyl amine (16.7 ml, 120.48 mmol) and after stirring 10 minutes, 2-bromo-1-phenylethanone (7.19 g, 36.14 mmol) was added and the reaction mixture was stirred at room temperature for about 4 hours. The reaction mixture was diluted with dichloromethane (300 ml), washed with aq. NaHCO₃ solution, brine and dried over Na₂SO₄. The organic layer was concentrated under reduced pressure to afford the title compound (12.0 g, 81%). The crude product was used in the next step without further purification. H¹ NMR (DMSO-d6, 300 MHz): δ 7.97 (t, J=8.3 Hz, 2H), 7.67 (t, J=8.3 Hz, 1H), 7.56 (t, J=8.3 Hz, 2H), 7.32 (m, 5H), 5.52 (ABq, 2H), 5.04 (ABq, 2H), 4.49 (m, 1H), 3.30-3.50 (m, 2H), 2.15 (m, 1H), 1.75-1.95 (m, 3H).

Step 2: Synthesis of (S)-benzyl 2-(4-phenyloxazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-benzyl 2-(2-oxo-2-phenylethyl) pyrrolidine-1,2-dicarboxylate (step 1, 12.0 g, 32.69 mmol) in acetic acid (150 ml), ammonium acetate (37.7 g, 490.3 mmol) was added at room temperature and heated at 120° C. for about 6 hours. Cooled to room temperature, the reaction mixture was concentrated, the residue was dissolved in dichloromethane (500 ml) and the organic layer was washed with aq. NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄, filtered and solvent was is evaporated. The residue was purified by column chromatography (eluted in 25% ethyl acetate/hexanes) to afford title compound (3.75 g, 33%). H¹ NMR (DMSO-d6, 300 MHz): δ 8.50 (s, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.30-7.45 (m, 5H), 7.13 (m, 3H), 4.90-5.12 (m, 3H), 3.50 (m, 2H), 2.30 (m, 1H), 1.95-2.10 (m, 3H).

Step 3: Synthesis of (S)-4-phenyl-2-(pyrrolidin-2-yl)oxazole

To a solution of (S)-benzyl 2-(4-phenyloxazol-2-yl)pyrrolidine-1-carboxylate (step 2, 3.5 g, 10.05 mmol) in EtOAc (40 ml) was added 10% Pd/C (700 mg) and stirred at room temperature under balloon pressure for about 24 hours. The catalyst was filtered through Celite bed and the filtrate was concentrated to afford the title compound (2.12 g, 98%). H¹ NMR (DMSO-D₆, 300 MHz): δ 8.49 (s, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.41 (t, J=8.3 Hz, 2H), 7.30 (t, J=8.3 Hz, 2H), 4.28 (m, 1H), 2.91 (m, 2H), 1.60-2.15 (m, 4H); Mass (ESI): 215.14 [M+H]⁺.

Intermediate 20: Preparation of (S)-4-tert-butyl-2-(pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate

Step 1: Synthesis of (S)-tert-butyl 2-(3,3-dimethyl-2-oxobutylcarbamoyl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (15.40 g, 71.69 mmol) in DMF (100 ml) at 0° C. was added DIPEA (37.40 ml, 220.5 mmol) and HATU (28.0 g, 71.69 mmol). After stirring 20 minutes, 1-amino-3,3-dimethylbutan-2-one hydrochloride (7.50 g, 49.66 mmol) was added and the reaction mixture was stirred at room temperature for about 18 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (2×250 ml) and washed with water (200 ml), saturated brine (100 ml) and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 mesh, 15-20% ethyl acetate in hexanes) to afford title compound (11.3 g, 51%). H¹ NMR (DMSO-d6, 300 MHz): δ 7.90 (broad t, 1H), 4.12 (m, 3H), 3.25-3.45 (m, 2H), 2.10 (m, 1H), 1.75-1.90 (m, 3H), 1.33 & 1.39 (2s, 9H), 1.11 (s, 9H).

Step 2: Synthesis of (S)-tert-butyl 2-(4-tert-butyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-tert-butyl 2-(3,3-dimethyl-2-oxobutylcarbamoyl) pyrrolidine-1-carboxylate (step 1, 11.3 g, 36.33 mmol) in xylene (130 ml), ammonium acetate (56.0 g, 726.6 mmol) was added at room temperature and heated at 140° C. for about 48 hours. The reaction mixture was cooled to room temperature, the pH was adjusted (pH˜7-8) with aq. NaHCO₃ solution and extracted with ethyl acetate (2×300 ml). The organic layer was washed with 1 N HCl (2×200 ml) and the aqueous layer was basified with 2N NaOH (200 ml), product was extracted with ethyl acetate (2×300 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (3.70 g, 35%). H¹ NMR (DMSO-d6, 300 MHz): δ 7.90 (broad peak, 1H), 6.54 (broad s, 1H), 4.65 (m, 1H), 3.25-3.45 (m, 2H), 2.10 (m, 1H), 1.75-1.90 (m, 3H), 1.33 & 1.39 (2s, 9H), 1.11 (s, 9H); Mass (ESI): 294.29 [M+H]⁴.

Step 3: Synthesis of(S)-4-tert-butyl-2-(pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate

A solution of (S)-tert-butyl 2-(4-tert-butyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 2.5 g, 8.53 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (10 ml) and stirred at room temperature for about 5 hours. Reaction mixture was concentrated, aqueous sodium bicarbonate solution was added to the residue and extracted with 10% methanol/dichloromethane (2×100 ml), washed with brine, dried over Na₂SO₄ and filtered. The solvents were evaporated under reduced pressure to afford title compound (1.34 g, 82%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.30 (broad peak, 1H), 6.49 (s, 1H), 4.04 (m, 1H), 2.70-3.0 (m, 2H), 2.0-2.50 (m, 4H), 1.11 (s, 9H); Mass (ESI: 194.17 [M+H]*.

Intermediate 21: Preparation of (S)-5-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of (S)-1-tert-butyl 2-(2-oxo-2-phenylethyl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(ter-butoxycarbonyl)pyrrolidine-2-carboxylic acid (10.0 g, 46.45 mmol) in DCM (100 ml) was added DIPEA (16.07 ml, 92.91 mmol) at 0° C. and after 10 minutes 2-bromo-1-phenylethanone (9.24 g, 46.45 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with dichloromethane (200 ml) and washed with water (200 ml), saturated brine (100 ml) and the organic layer was concentrated under reduced pressure to afford the desired compound (15.48 g, Yield: 100%). The crude product was used in the next step without further purification.

Step 2: Synthesis of(S)-tert-butyl 2-(4-phenyl-H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-tert-butyl 2-(2-oxo-2-phenylethyl) pyrrolidine-1,2-dicarboxylate (step 1, 15.40 g, 46.24 mmol) in toluene (180 ml), ammonium acetate (30.29 g, 393.09 mmol) was added at room temperature and refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (200 ml), water and the organic layer was washed with 0.5N HCl (2×150 ml). Aqueous layer was basified with 2N NaOH (150 ml), the precipitated solid was filtered and dried to afford the desired compound (11.6 g, Yield: 80%) as an off white solid. HPLC purity: 99%.

Step 3: Synthesis of (S)-5-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of (S)-tert-butyl 2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 2.0 g, 6.6 mmol) in TFA: DCM (1:2, 15 mL) was stirred at 0° C.—room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated and the crude product was used in the next step without further purification (2.1 g).

Intermediate 22: Preparation of(S)-5-(4-methoxyphenyl)-2-(pyrrolidin-2-yl)-H-imidazole

Step 1: Synthesis of 1-(tert-butyl) 2-(2-(4-methoxyphenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (tert-butoxycarbonyl)-L-proline (5.0 g, 23.36 mmol) in DCM (75 mL), DIPEA (8.1 mL, 46.72 mmol, 1.0 eq) was added at 0° C. After 10 minutes 2-bromo-1-(4-methoxyphenyl)ethan-1-one (5.3 g, 23.36 mmol, 1.0 eq) was added and the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure to afford the title compound (7.5 g, yield: 89%). The obtained crude product was used in the next step without further purification.

Step 2: Synthesis of tert-butyl (S)-2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-(2-(4-methoxyphenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate (step 1, 7.5 g, 20.71 mmol, 1.0 eq) in toluene (75 mL), ammonium acetate (12.76 g, 165.74 mmol, 8.0 eq) was added at room temperature and refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and the organic layer was washed with 0.5 N hydrochloric acid. Aqueous layer was basified with 2N NaOH (pH 10-11) and extracted with ethyl acetate. The organic layer was washed with water, dried over Na₂SO₄, filtered and solvent was evaporated under reduced pressure to provide a light yellow solid was taken in to hexane, stirred for one hour and filtered (4.0 g, yield: 59.0%).

Step 3: Synthesis of (S)-5-(4-methoxyphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 2.8 g, 8.4 mmol, 1.0 eq) in Dioxane in HCl (25 mL), stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated to afford the title compound (1.8 g, yield: 95.0%) as a semi solid and proceed for next step without further purification.

The following Intermediate 22a prepared as described in the above Intermediate 22.

Intermediate 22a: Preparation of(S)-5-(4-methoxyphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

Intermediate 23: Preparation of (S-5-(4-chlorophenyl-2-(pyrrolidin-2-yl-1H-imidazole

Step 1: Synthesis of 1-(tert-butyl) 2-(2-(4-chlorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (tert-butoxycarbonyl)-L-proline (5 g, 23.36 mmol) in DCM (50 mL), DIPEA (8.05 mL, 46.72 mmol) was added at 0° C. and after 10 minutes 2-bromo-1-(4-chlorophenyl)ethan-1-one (5.4 g, 23.36 mmol) was added. Then the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure to afford the title compound (8.0 g, yield: 94%). The crude product was used in the next step without further purification.

Step 2: Synthesis of tert-butyl (S)-2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-(2-(4-chlorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate (step 1, 8.0 g, 21.85 mmol) in toluene (8 mL), ammonium acetate (13.4 g, 174.8 mmol) was added at room temperature and refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and the organic layer was washed with 0.5 N hydrochloric acid. Aqueous layer was basified with 2N NaOH (pH 10-11) and extracted with ethyl acetate. The organic layer was washed with water, dried over Na₂SO₄, filtered and the solvent was evaporated under reduced pressure to afford the title compound (5.0 g, yield: 67.0%).

Step 3: Synthesis of (S)-5-(4-chlorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 3.0 g, 8.64 mmol) in Dioxane.HCl (20 mL), stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated and the crude was dissolved in DCM and proceeds for next step without further purification (2.0 g, yield: 95.0%).

Intermediate 24: Preparation of (S)-3-(5-phenyl-1H-imidazol-2-yl)piperidin-1-ium chloride

Step 1: Synthesis of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid

To a stirred solution of (S)-(+)-3-piperidine carboxylic acid (5.0 g, 38.75 mmol, 1.0 eq) in 1,4-dioxane (50 ml) was added 1N NaOH (25 mL) and (Boc)₂O (12.6 gr, 58.1 mmol). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was extracted with EtOAc (100 mL), collected aqueous layer was acidified with 1N HCl (p^(H)˜2 to 3) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue (5.3 gr, yield: 56%) was used for next step without further purification. ¹H NMR (300 MHz, DMSO): δ 12.36 (s, 1H), 3.9 (bs, 1H), 3.68 (d, J=12.0 Hz, 1H), 3.11-2.76 (m, 2H), 2.36-2.23 (m, 1H), 1.97-1.84 (m, 1H), 1.59-1.42 (m, 2H), 1.38 (s, 9H), 1.37-1.26 (m, 1H); ES Mass: [M+23]⁺ 252.09.

Step 2: Synthesis of 1-(tert-butyl) 3-(2-oxo-2-phenylethyl) (S)-piperidine-1,3-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (step 1, 5.3 g, 23.1 mmol, 1.0 eq) in CH₂Cl₂ (53 ml) was added DIPEA (11.93 gr, 92.45 mmol) and 2-bromoacetophenone (13.02 gr, 6.07 mmol). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water. The aqueous layer was extracted with CH₂Cl₂ (2×100 ml). The combined organic layers were washed with aq.NaHCO₃, water, and brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue (6.0 gr, yield: 74.7%) was used for next step without further purification. ¹H NMR (300 MHz, CDCl3): δ 7.9 (d, J=7.2 Hz, 2H), 7.61 (t, J=7.5 Hz, 1H), 7.51-7.46 (m, 2H), 5.42-5.27 (m, 2H), 4.24 (s, 1H), 3.96 (d, J=10.8 Hz, 1H), 3.06 (t, J=10.8 Hz, 1H), 2.77 (t, J=11.4 Hz, 1H), 2.78-2.6 (m, 1H), 2.21-2.15 (m, 1H), 1.78-1.71 (m, 2H), 1.46 (s, 10H); ES Mass: [M+Na]⁺ 370.22.

Step 3: Synthesis of tert-butyl (S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 3-(2-oxo-2-phenylethyl) (S)-piperidine-1,3-dicarboxylate (step 2, 12.0 gr, 34.56 mmol) in toluene (120 mL) added NH₄OAc (21.3 gr, 276.5 mmol) and stirred the reaction mixture for 12 hours at 90° C. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 30% EtOAc: n-Hexane as an eluent to afford the desired product (6.0 g, yield: 53.1%) as brown color syrup. ¹H NMR (300 MHz, DMSO): δ 11.93 (bs, 1H), 7.7 (d, J=7.2 Hz, 2H), 7.49 (bs, 1H), 7.33 (t, J=7.2 Hz, 2H), 7.18-7.13 (m, 1H), 4.14 (bs, 1H), 3.92 (d, J=12.6 Hz, 1H), 3.06-3.01 (m, 1H), 2.78-2.73 (m, 2H), 2.09-2.02 (m, 1H), 1.76-1.7 (m, 2H), 1.4 (s, 9H), 1.39-1.36 (m, 1H); ES Mass: [M+H]⁺328.16.

Step 4: Synthesis of (S)-3-(5-phenyl-1H-imidazol-2-yl)piperidin-1-ium chloride

To a stirred solution of tert-butyl (S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate (step 3, 6.0 g, 18.33 mmol, 1.0 eq) in CH₂Cl₂ (30 ml) was added 4M HCl in dioxane (60 mL). The reaction mixture was stirred at room temperature for 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated under reduced pressure to get the residue (4.7 gr, yield: 97.5%) and used directly for next step without further purification.

Intermediate 25: Preparation of 4-(5-phenyl-1H-imidazol-2-yl)piperidine hydrochloride

Step 1: Synthesis of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate

To a stirred solution of Ethyl 4-piperidinecarboxylate (10.0 g, 63.61 mmol, 1.0 eq) in CH₂Cl₂ (100 ml) was added Et₃N (12.8 g, 127.21 mmol, 2.0 eq) and (Boc)₂O (16.6 gr, 76.33 mmol). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water. The aqueous layer was extracted with CH₂Cl₂ (2×250 ml). The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue (15 gr, yield: 92%) was used for next step without further purification.

Step 2: Synthesis of 1-(tert-butoxycarbonyl piperidine-4-carboxylic acid

To a stirred solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (step 1, 15.0 g, 58.29 mmol, 1.0 eq) in THF:MeOH (1:1, 150 ml) was added 2N NaOH solution (150 mL). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was washed with EtOAc (150 mL). The aqueous layer was acidified with 1N HCl at 0° C. and extracted with CH₂Cl₂ (2×250 ml). The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue (65 gr, yield: 45%) was used for next step without further purification. ¹H NMR (300 MHz, CDCl₃+D₂O): δ 4.05-4.01 (m, 2H), 2.89-2.82 (m, 2H), 2.53-2.46 (m, 1H), 1.94-1.89 (m, 2H), 1.71-1.58 (m, 2H), 1.46 (s, 9H); ES Mass: [M−H]⁺ 228.05.

Step 3: Synthesis of 1-(tert-butyl) 4-(2-oxo-2-phenylethyl) piperidine-1,4-dicarboxylate

To a stirred solution of 1-(tert-butoxycarbonyl) piperidine-4-carboxylic acid (step 2, 15.0 g, 65.42 mmol, 1.0 eq) in CH₂Cl₂ (150 ml) was added DIPEA (17.08 gr, 130.84 mmol) and 2-bromoacetophenone (13.02 gr, 65.42 mmol). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water. The aqueous layer was extracted with EtOAc (2×250 ml). The combined organic layers were washed with aq.NaHCO₃, water, brine and were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue (21.0 gr, yield: 93.4%) was used for next step without further purification. ¹H NMR (300 MHz, CDCl₃): δ 7.91-7.88 (m, 2H), 7.63-7.58 (m, 1H), 7.51-7.46 (m, 2H), 5.35 (s, 2H), 4.03 (d, J=12.6 Hz, 2H), 2.92 (t, J=11.1 Hz, 2H), 2.7-2.6 (m, 1H), 1.97 (dd, J=3.3, 13.5 Hz, 2H), 1.81-1.68 (m, 2H), 1.46 (s, 9H); ES Mass: [M+Na]⁺ 370.05 (100%).

Step 4: Synthesis of tert-butyl 4-(5-phenyl-H-imidazol-2-yl)piperidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 4-(2-oxo-2-phenylethyl) piperidine-1,4-dicarboxylate (step 3, 12.0 gr, 34.56 mmol) in toluene (120 mL) added NH₄OAc (21.3 gr, 276.5 mmol) and stirred the reaction mixture for 12 hours at 90° C. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 30% EtOAc: n-Hexane as an eluent to afford the desired product (6.0 g, yield: 53.1%) as brown colour syrup. ¹H NMR (300 MHz, CDCl₃): δ 8.61 (bs, 1H), 7.65 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.2 Hz, 2H), 7.24-7.19 (m, 2H), 4.17 (d, J=12.9 Hz, 2H), 3.03-2.95 (m, 1H), 2.8 (t, J=12.3 Hz, 2H), 1.97 (d, J=11.1 Hz, 2H), 1.77-1.63 (m, 2H), 1.46 (s, 9H); ES Mass: [M+H]⁺ 328.1 (100%).

Step 5: Synthesis of 4-(5-phenyl-1H-imidazol-2-yl)piperidine hydrochloride

To a stirred solution of tert-butyl 4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carboxylate (step 4, 2.2 g, 6.72 mmol, 1.0 eq) in CH₂Cl₂ (22 ml) was added 4M HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated under reduced pressure to get the residue (1.52 gr) and used directly for next step without further purification.

Intermediate 26: Preparation of 4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine

Step 1: Synthesis of 1-benzylpiperidin-4-one oxime

To a stirred solution of 1-benzylpiperidin-4-one (4.0 g, 21.16 mmol, 1.0 eq) in EtOH (40 ml) was added Hydroxylamine hydrochloride (2.5 g, 35.97 mmol, 1.7 eq). The reaction mixture was heated to 50° C., 10M aq.Na₂CO₃ solution (1.5 ml) was slowly added and refluxed for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (200 ml) and extracted with CH₂Cl₂ (2×100 ml). The combined organic layers were washed with water, brine solution, dried over Na₂SO₄, filtered and evaporated under reduced pressure to obtain the desired product (3.3 g, yield: 76%) as a colourless oil. ¹H NMR (300 MHz, CDCl₃): δ ppm 8.06 (brs, 1H), 7.36-7.26 (m, 5H), 3.55 (s, 2H), 2.65 (t, J=6.0 Hz, 2H), 2.60-2.50 (m, 4H), 2.35 (t, J=6.0 Hz, 2H); ES MS: [M+H]⁺ 205.1 (1000%).

Step 2: Synthesis of 1-benzylpiperidin-4-amine

To a stirred solution of 1-benzylpiperidin-4-one oxime (step 1, 3.3 g, 16.17 mmol, 1.0 eq) in methanol (15 ml) was added Raney Nickel (0.5 g) and 7N Methanolic ammonia solution (30 ml). The reaction mixture was stirred at room temperature under hydrogen atmosphere (balloon pressure) for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and washed with methanol (50 ml). The filtrate was evaporated under reduced pressure to obtain the desired product (2.9 g, 96% yield) as colourless oil. ¹H NMR (300 MHz, DMSO-d6): δ ppm 7.37-7.17 (m, 5H), 3.50-3.10 (m, 4H), 2.76-2.62 (m, 2H), 1.98-1.82 (m, 2H), 1.70-1.52 (m, 2H), 1.30-1.10 (m, 3H); ES MS: [M+H]⁺ 191.2 (100%).

Step 3: Synthesis of N-(1-benzylpiperidin-4-yl)isobutyramide

To a stirred solution of 1-benzylpiperidin-4-amine (step 2, 2.9 g, 15.26 mmol, 1.0 eq) in CH₂Cl₂ (40 ml) at 0° C. was added triethylamine (5.46 ml, 39.4 mmol, 3.0 eq) and isobutyryl chloride (1.62 g, 15.2 mmol, 1.0 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was washed with water (2×50 ml), dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 2% methanol: dichloromethane as an eluent to obtain the desired product (2.7 g, yield: 68.1%) as a colourless solid. ¹H NMR (300 MHz, CDCl₃): δ ppm 7.37-7.20 (m, 5H), 5.26 (d, J=6.6 Hz, 1H), 3.87-3.72 (m, 1H), 3.49 (s, 2H), 2.86-2.76 (m, 2H), 2.35-2.25 (m, 1H), 2.11 (t, J=11.1 Hz, 2H), 1.95-1.85 (m, 2H), 1.50-1.35 (m, 2H), 1.13 (d, J=6.9 Hz, 6H); ES MS: [M+H]⁺ 261.2 (100%), [M+Na]⁺ 283.1 (50%).

Step 4: Synthesis of (E)-N′-(1-(1-benzylpiperidin-4-ylimino)-2-methylpropyl)acetohydrazide

To a stirred solution of PCl₅ (2.8 g, 13.49 mmol, 1.3 eq) in CH₂Cl₂ (35 ml) at 0° C. was slowly added N-(1-benzylpiperidin-4-yl)isobutyramide (step 3, 2.7 g, 10.38 mmol, 1.0 eq) dissolved in CH₂Cl₂ (10 ml). The reaction mixture was stirred at 0° C. for about 15 min. and at room temperature for about 2 hours. A freshly prepared solution of acetic hydrazide [prepared by adding tert-amyl alcohol (11 ml) and CH₃CN (22 ml) to acetic hydrazide (1.69 g, 22.8 mmol, 2.2 eq) and the total clear solution was concentrated to ¼ volume at 40° C. under vacuum] was added to the reaction mixture and stirred at room temperature for overnight. The reaction mixture was cooled to O C, basified with 10M aq. NaOH solution to pH˜9-10 and extracted with CH₂Cl₂ (2×100 ml). The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure to obtain desired product (Wt: 3.5 g) as a light brown oil, which is used as such for next step without further purification.

Step 5: Synthesis of 1-benzyl-4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine

To a stirred solution of (E)-N′-(1-(1-benzylpiperidin-4-ylimino)-2-methylpropyl) acetohydrazide (step 4, 3.5 g, 11.07 mmol, 1.0 eq) in tert-Amyl alcohol (15 ml) was added acetic acid (1.23 ml, 22.15 mmol, 2.0 eq). The reaction mixture was heated to reflux for 3 h. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0° C., basified with aq. 2N NaOH to pH˜10, two layers were separated and the aqueous layer was extracted with EtOAc (2×100 ml). The combined organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 2% methanol: dichloromethane as an eluent to give the desired product (1.6 g, yield: 53%) as a white solid. ¹H NMR (300 MHz, CDCl₃+D₂O): 5 ppm 7.37-7.29 (m, 5H), 3.98-3.80 (m, 1H), 3.57 (s, 2H), 3.12-2.97 (m, 3H), 2.54 (s, 3H), 2.30-2.05 (m, 4H), 1.86-1.76 (m, 2H), 1.40 (d, J=6.9 Hz, 6H); ES MS: [M+H]⁺ 299.1 (100%), [M+Na]⁺ 321.1 (30%).

Step 6: Synthesis of 4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine

To a suspension of 10% Pd/C (0.3 g) in EtOAc (10 ml) was added a solution of 1-benzyl-4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine (step 5, 1.6 g, 5.36 mmol, 1.0 eq) in MeOH (50 ml) and para-toluenesulfonic acid (0.020 g, 5.30 mmol, 1.0 eq). The reaction mixture was hydrogenated at 60 psi pressure for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and washed with EtOAc: Methanol (1:5, 60 ml). The filtrate was evaporated under reduced pressure to obtain desired product (Wt: 2.2 g) as a colourless solid. ES MS: [M+H]⁺ 209.1 (100%).

Intermediate 27: Preparation of (S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-ium chloride

Step 1: Synthesis of L-proline methyl ester

To a solution of L-Proline (1 mol) in MeOH was added drop wise SOCl₂ at 0° C. After addition temperature was raised to refluxed for about 8 hours, the crude mixture was concentrated under reduced pressure. Used in the next step without any further purification.

Step 2: Synthesis of (2S)—N-(tert-Butoxycarbonyl)proline Methyl Ester

To a solution of L-Proline methyl ester (step 1, 1 mol) in CH₂Cl₂ was added Boc₂O (1.5 mol), Et₃N (3 mmol), and DMAP (1 mol) at 0° C. under Ar. After 18 hours, the crude mixture was washed with aqueous HCl 0.5 M, saturated aqueous NaHCO₃ solution, H₂O, and brine. The organic phase was dried over Na₂SO₄, filtered, concentrated in vacuo, and the residue was recrystallized using ether to afford compound.

Step 3: Synthesis of (2S)—N-(tert-Butoxycarbonyl)pyrrolidine-2-carboxamide

(2S)—N-(tert-Butoxycarbonyl) proline methyl ester (step 2) was heated in a mixture of THF and 28% aqueous NH₃ (2/9, v/v) at 60° C. for about 18 hours under Ar. The reaction mixture was concentrated to give Boc-L-Pro-NH₂, used in the next step without any further purification

Step 4: Synthesis of (2S)—N-(tert-Butoxycarbonyl)-pyrrolidine-2-carbonitrile

TFA anhydride (1.5 mol) was added to a solution of (2S)—N-(tert-butoxycarbonyl) pyrrolidine-2-carboxamide (step 3, 1 mol) and Et₃N (2.5 mol) in dry THF (10V) under Ar at 0° C. The reaction was stirred at 0° C. for another 6 hours. After addition of CH₂Cl₂, the organic phase was washed with a saturated aqueous NaHCO₃ solution, dried over Na₂SO₄, filtered, and concentrated in vacuum to afford (yield: 86%, brown oil) used in the next step without any further purification.

Step 5: Synthesis of tert-butyl-2-(5-phenyl-4H-1, 2, 4-triazole)pyrrolidine-1-carboxylate

To a solution of (2S)—N-(tert-butoxycarbonyl)-pyrrolidine-2-carbonitrile (step 4, 1 mol) in MeOH was added K₂CO₃ followed benzohydrazide. After addition temperature was raised to reflux for about 15 hours, the crude mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford desired product.

Step 6: Synthesis of (S)-2-(5-phenyl-4H-1, 2, 4-triazol-3-yl)pyrrolidin-1-ium chloride

To a stirred solution of tert-butyl (S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate (step 5, 4.0 g, 12.73 mmol, 1.0 eq) in CH₂Cl₂ (20 ml) was added 4M HCl in dioxane (40 mL). The reaction mixture was stirred at room temperature for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was concentrated under reduced pressure to get the residue (3.0 gr, yield: 94.3%) and used directly for next step without further purification.

Intermediate 28: Preparation of (S)-4-(3-fluoro-4-methoxyphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of (S)-1-tert-butyl 2-(2-(3-fluoro-4-methoxyphenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (4.35 g, 20.2 mmol) in DCM (50 ml) at 0° C. was added DIPEA (10.8 ml, 60.7 mmol) and after stirring 10 minutes, 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (5.0 g, 20.2 mmol) was added and the reaction mixture was stirred at room temperature for about 18 hours. The reaction mixture was diluted with dichloromethane (200 ml), washed with water, saturated brine, dried over Na₂SO₄, filtered and the organic layer was concentrated under reduced pressure to afford the title compound (crude 7.5 g, 97%). The crude product was used in the next step without further purification.

Step 2: Synthesis of (S)-tert-butyl 2-(4-(3-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-tert-butyl 2-(2-(3-fluoro-4-methoxyphenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (step 1, 7.5 g, 19.68 mmol) in toluene (60 ml), ammonium acetate (15.15 g, 196.8 mmol) was added at room temperature and refluxed for about 18 hours. Cooled to room temperature, the reaction mixture was diluted with ethyl acetate (200 ml) and the organic layer was washed with 1 N HCl (2×100 ml). Aqueous layer was basified (pH=8-9) with 2N NaOH, extracted with ethyl acetate (2×200 ml), dried over Na₂SO₄, filtered and concentrated to afford title compound (3.65 g, 51%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.84 (bs, 1H), 7.51 (m, 2H), 7.42 (s, 1H), 7.11 (t, J=9.3 Hz, 1H), 4.78 (m, 1H), 3.84 (s, 3H), 3.52 (m, 1H), 3.36 (m, 1H), 1.88-2.25 (m, 4H), 1.34 & 1.16 (2s, 9H).

Step 3: Synthesis of (S)-4-(3-fluoro-4-methoxyphenyl)-2-(pyrrolidin-2-yl)-H-imidazole

To a solution of (S)-tert-butyl 2-(4-(3-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 3.65 g, 10.1 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (9.93 ml) and stirred at room temperature for about 16 hours. Reaction mixture was concentrated under reduced pressure to afford title compound as a TFA salt (3.8 g) which was used in the next step without further purification.

Intermediate 29: Preparation of (S)-3-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine 1-oxide

To a solution of (S)-3-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine (Intermediate 5, 0.25 g, 0.30 mmol, 1.0 eq) dissolved in DCM and was added MCPBA (0.063 g, 0.366 mmol, 1.5 eq) under N₂ atmosphere at 0° C. The reaction mixture was allowed to stir at room temperature for about 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with saturated sodium sulphite, water followed by saturated brine, dried over Na₂SO₄ and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 10% methanol: dichloromethane as an eluent to afford the title compound.

Intermediate 30: Preparation of 2,2,2-trifluoro-1-((2S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)-1λ⁴-pyrrolidin-1-yl)ethan-1-one

Step 1: Synthesis of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a suspension of lithium aluminium hydride (17.6 g, 0.46 mmol, 2.0 eq) in THF (500 ml) at 0° C., (tert-butoxycarbonyl)-L-proline (50 g, 0.23 mmol, 1.0 eq) in THF (500 ml) was added dropwise over a period of about 1 hour. The reaction was allowed to stir at room temperature for about 90 minutes. After completion of the reaction (monitored by TLC), the reaction mass was quenched at 0° C. using saturated sodiumsulphate, followed by addition of ethylacetate. The reaction mass was filtered over celite. The organic layer from the filtrate was separated and compound was extracted from water layer with ethylacetate. Combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude compound was purified by column chromatographic technique to afford the desired compound (24 g, yield: 51%), which was used for the next step without further purification. ¹H NMR (DMSO, 300 MHz): δ 4.67 (t, 1H, J=5.5 Hz), 3.65 (bs, 1H), 3.50-3.43 (m, 1H), 3.26-3.18 (m, 3H), 1.82-1.70 (m, 4H), 1.39 (s, 9H).

Step 2: Synthesis of tert-butyl (S)-2-formylpyrrolidine-1-carboxylate

DMSO (1.9 ml, 24.87 mmol, 2 eq) dissolved in CH₂Cl₂ (10 ml) was slowly added in about 40 minutes to a solution of oxalyl chloride (1.4 ml, 11.65 mmol, 1.2 eq) in CH₂Cl₂ (20 ml) at −78° C. Afterwards a solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (step 1, 2.75 g, 13.68 mmol, 1 eq) in CH₂Cl₂(30 ml) was added to the mixture. After stirring for about 75 minutes, DIPEA (10.0 ml, 77.51 mmol, 4 eq) was added and the mixture was allowed to warm to room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was washed 3 times with 0.5M HCl (aq, 40 ml), 3 times with water (70 ml) and once with saturated NaCl solution (70 ml). The organic layer was dried over anhydrous Na₂SO₄ and concentrated to afford the desired compound (1.6 g, yield: 58.8%) as a white solid. ¹H NMR (CDCl₃, 300 MHz): δ 1.52 (s, 9H), 1.92-2.16 (m, 4H), 3.42-3.60 (m, 1H), 4.00-4.20 (m, 1H), 9.45-9.55 (m, 1H); MS(ESI): m/z 199 (M+H)⁺.

Step 3: Synthesis of tert-butyl (S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of tert-butyl (S)-2-formylpyrrolidine-1-carboxylate (step 2, 1.6 g, 8.03 mmol, 1.0 eq) in MeOH (20 ml) was added 3,3-dibromo-1,1,1-trifluoropropan-2-one (3.4 ml, 99.03 mmol, 3.7 eq) and aq. NH₃ (1.1 ml 4.16 mmol, 1.09 eq) in one portion. The reaction mixture was stirring at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the residue was purified by column chromatography by using 25% Ethyl acetate: Hexane as an eluent to afford the desire product (1.9 g, yield: 79.1%) as a white solid. ¹H NMR (DMSO, 300 MHz): δ 1.13-1.38 (m, 10H), 1.82-1.86 (m, 2H), 2.21-2.23 (m, 1H), 3.36 (s, 1H), 3.50 (s, 1H), 4.69-4.81 (s, 1H), 7.59-7.63 (m, 1H), 12.40-12.48 (m, 1H); MS(ESI): m/z 306.20 (M+H)⁺.

Step 4: Synthesis of 2,2,2-trifluoro-1-((2S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)-1λ⁴-pyrrolidin-1 yl)ethan-1-one

TFA (2.3 ml, 20.1 mmol, 5 eq) was added to a solution of tert-butyl (S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 1.9 g, 6.2 mmol, 1) in DCM (30 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure to give the title compound, which was directly used in the next step.

Intermediate 31: Preparation of (S)-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole TFA salt

Step 1: Synthesis of (S)-tert-butyl 2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (7.13 g, 33.3 mmol) in DMF (50 ml) were added DIPEA (19.6 ml, 110.8 mmol), EDC (6.4 g, 33.3 mmol) and HOBt (4.47 g, 33.3 mmol). After stirring about 10 minutes, o-phenylenediamine (5.0 g, 27.7 mmol) was added and the reaction mixture was stirred at room temperature for about 18 hours, then at 100° C. for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water, extracted with ethyl acetate (200 ml), washed with saturated brine (100 ml) and the organic layer was concentrated under reduced pressure to afford title compound (2.0 g, yield: 21%). The crude product was used in the next step without further purification. H¹ NMR (DMSO-D₆, 300 MHz): δ 12.22 (broad s, 1H), 7.47 (m, 2H), 7.11 (m, 2H), 4.92 (m, 1H), 3.60 (m, 1H), 3.39 (m, 1H), 2.30 (m, 1H), 1.85-2.03 (m, 3H), 1.39 & 1.06 (2s, 9H).

Step 2: Synthesis of(S)-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole TFA salt

To a solution of (S)-tert-butyl 2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (step 1, 2.0 g, 6.90 mmol) in DCM (20 ml) was added trifluoroacetic acid (2.6 ml, 34.84 mmol) and stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford title compound (2.0 g, yield: 100%) as a TFA salt. H¹ NMR (DMSO-D₆, 300 MHz): δ 9.8 (bs, 1H), 9.0 (broad peak, 1H), 7.63 (m, 2H), 7.27 (m, 2H), 4.98 (m, 1H), 3.3-3.45 (m, 2H), 2.05-2.25 (m, 4H).

Intermediate 32: Preparation of(S)-5-(2,4-difluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of 2-bromo-1-(2,4-difluorophenyl)ethan-1-one

To the stirred solution of 2,4-difluoroacetophenone (10 g, 64.10 mmol) in 200 mL of MeOH at 0° C. was added Bromine (3.3 mL, 20.62 mmol) (dropwise addition) and stirred for about 30 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The obtained solid was filtered and washed with n-hexane then dried and proceeded for next step (wt: 14.0 g).

Step 2: Synthesis of 1-(tert-butyl) 2-(2-(2,4-difluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (12.8 g, 59.82 mmol) in DCM (120 mL), DIPEA (20.47 mL, 158.75 mmol) was added at 0° C. temperature and after 10 minutes 2-bromo-1-(2,4-difluorophenyl)ethan-1-one (step 1, 14 g, 59.82 mmol) was added. Then the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was proceeded to next step without further purification (wt: 18.0 g).

Step 3: Synthesis of tert-butyl (S)-2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-(2-(2,4-difluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate (step 2, 18.0 g, 48.78 mmol) in Toluene (180 mL), ammonium acetate (37.56 g, 487.80 mmol) was added at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc, washed with water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 8.0 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.1-7.5 (m, 3H), 7.61-7.63 (m, 2H), 4.98-5.00 (d, 1H, j=6 Htz), 3.42 (s, 2H), 3.01 (s, 1H), 2.14-2.17 (m, 4H), 1.50 (s, 9H); Mass: 349 [M+1]⁺ 350 (100%).

Step 4: Synthesis of (S)-5-(2,4-difluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 2.1 g, 6.0 mmol) in TFA:DCM (1:2, 30 mL) stirred at 0° C.—room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and proceeded for next step without further purification (wt: 1.6 g).

Intermediate 33: Preparation of (S)-5-(2-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

Step 1: Synthesis of 2-bromo-1-(2-fluorophenyl)ethan-1-one

To the stirred solution of 2-fluoroacetophenone (10 g, 72.46 mmol) in 200 mL of MeOH at 0° C. was added Bromine (3.7 mL, 23.37 mmol) (dropwise addition) and stirred for about 30 minutes and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude product was dissolved in n-hexane and stirred for about 30 minutes. The obtained solid was filtered and washed with n-hexane then dried and proceeded for next step (wt: 14.0 g).

Step 2: Synthesis of 1-(tert-butyl) 2-(2-(2-fluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (13.9 g, 64.65 mmol) in DCM (120 mL), DIPEA (22.39 mL, 173.64 mmol) was added at 0° C. temperature and after 10 minutes 2-bromo-1-(2-fluorophenyl)ethan-1-one (step 1, 14 g, 65.1 mmol) was added. Then the reaction mixture was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was proceeded to next step without further purification (wt: 18.0 g).

Step 3: Synthesis of tert-butyl (S)-2-(5-(2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of 1-(tert-butyl) 2-(2-(2-fluorophenyl)-2-oxoethyl) (S)-pyrrolidine-1,2-dicarboxylate (step 2, 18.0 g, 51.28 mmol) in Toluene (180 mL) ammonium acetate (39.48 g, 512.8 mmol) was added at room temperature and refluxed for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the crude was diluted with EtOAc, washed with water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 20% EtOAc in hexane) to afford the title compound (wt: 8.0 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.1-7.5 (m, 3H), 7.61-7.63 (m, 2H), 4.98-5.00 (d, 1H, j=6 Htz), 3.42 (s, 2H), 3.01 (s, 1H), 2.14-2.17 (m, 4H), 1.50 (s, 9H); Mass: 331 [M+1]⁺ 332 (100%).

Step 4: Synthesis of (S)-5-(2-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole

A solution of tert-butyl (S)-2-(5-(2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 2.1 g, 6.4 mmol) in TFA:DCM (1:2, 30 mL) stirred at 0° C.—room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and proceeded for next step without further purification (wt: 1.4 g).

Intermediate 34: Preparation of (S)-4-(3-chlorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole TFA salt

Step 1: Synthesis of (S)-1-tert-butyl 2-(2-(3-chlorophenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate

To a stirred solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (12.8 g, 60.1 mmol) in DCM (140 ml) at 0° C. was added triethyl amine (25.0 ml, 180.3 mmol) and after stirring about 10 minutes, 2-bromo-1-(3-chlorophenyl)ethanone (14.0 g, 60.1 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with dichloromethane (200 ml), washed with water (200 ml), saturated brine (100 ml), the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (16.0 g, yield: 73%). The crude product was used in the next step without further purification. H¹ NMR (DMSO-D₆, 300 MHz): δ 8.02 (m, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.60 (t, 9.3 Hz, 1H), 5.60 (ABq, 2H), 4.33 (m, 1H), 3.39 (m, 2H), 2.30 (m, 1H), 2.12 (m, 1H), 1.86 (m, 2H), 1.39 & 1.36 (2s, 9H).

Step 2: Synthesis of (S)-tert-butyl 2-(4-(3-chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-1-tert-butyl 2-(2-(3-chlorophenyl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate (step 1, 16.0 g, 43.71 mmol) in toluene (150 ml), ammonium acetate (33.70 g, 437.15 mmol) was added at room temperature and resulting reaction mixture was refluxed for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added, extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2×100 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×100 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford the title compound (4.7 g, yield: 31%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.98 (broad s, 1H), 7.77 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.33 (t, J=9.0 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 4.80 (m, 1H), 3.35 (m, 2H), 2.20 (m, 1H), 1.90 (m, 2H), 1.73 (m, 1H), 1.39 & 1.15 (2s, 9H).

Step 3: Synthesis of (S)-4-(3-chlorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole TFA salt

To a solution of (S)-tert-butyl 2-(4-(3-chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 2, 2.0 g, 5.78 mmol) in DCM (20 ml) was added trifluoroacetic acid (5.7 ml, 74.51 mmol) and stirred at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford the title compound (2.0 g) as a TFA salt. H¹ NMR (DMSO-D₆, 300 MHz): δ 11.99 (broad peak, 1H), 7.99 (bs, 1H), 7.78 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.34 (t, J=8.7 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 4.20 (m, 1H), 2.8-3.02 (m, 2H), 2.10 (m, 1H), 1.70-1.95 (m, 3H).

Intermediate 35: Preparation of (3R,5S)-5-(4-phenyl-1H-imidazol-2-yl)pyrrolidin-3-ol TFA salt

Step 1: Synthesis of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-hydroxypyrrolidine-1,2-dicarboxylate

To a stirred solution (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (Intermediate 9-step 1, 20.0 g, 86.9 mmol) in DCM (400 ml) at 0° C. was added triethyl amine (36.3 ml, 26.0 mmol) and after stirring about 10 minutes, 2-bromo-1-phenylethanone (19.0 g, 95.6 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with dichloromethane (200 ml). The organic layer was washed with aqueous NaHCO₃ solution, saturated brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound (25.0 g, yield: 83%). The crude product was used in the next step without further purification.

H¹ NMR (DMSO-D₆, 300 MHz): δ 7.99 (d, J=8.0 Hz, 2H), 7.71 (t, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 2H), 5.56 (ABq, 2H), 5.16 (m, 1H), 4.36 (m, 2H), 3.27-3.45 (m, 2H), 2.20 (m, 2H), 1.39 & 1.36 (2s, 9H).

Step 2: Synthesis of (2S,4R)-tert-butyl 4-hydroxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-hydroxy pyrrolidine-1,2-dicarboxylate (step 1, 20.0 g, 57.5 mmol) in toluene (200 ml), ammonium acetate (44.25 g, 575.0 mmol) was added at room temperature and resulting reaction mixture was refluxed for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (2×250 ml) and the organic layer was washed with 1N HCl (2×200 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×200 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford the title compound (14.0 g, yield: 74%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.92 (bs, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.31 (m, 2H), 7.15 (m, 11H), 5.06 (m, 1H), 4.84 (m, 1H), 4.40 (m, 1H), 3.60 (m, 1H), 3.36 (m, 1H), 2.0-2.24 (m, 2H), 1.38 & 1.11 (2s, 9H).

Step 3: Synthesis of (3R,5S)-5-(4-phenyl-1H-imidazol-2-yl)pyrrolidin-3-ol TFA salt

To a solution of (2S,4R)-tert-butyl 4-hydroxy-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (step 2, 2.0 g, 6.1 mmol) in DCM (20 ml) was added trifluoroacetic acid (4.6 ml, 61.60 mmol) and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford the title compound (2.0 g, yield: 100%) as a TFA salt. H¹ NMR (DMSO-D₆+D₂O, 300 MHz): δ 8.05 (s, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.40-7.57 (m, 3H), 5.18 (m, 1H), 4.67 (m, 1H), 3.50 (m, 1H), 3.33 (m, 1H), 2.51 (m, 2H).

Intermediate 36: Preparation of 2-((2S,4R)-4-isopropoxypyrrolidin-2-yl)-4-phenyl-1H-imidazole TFA salt

Step 1: Synthesis of (2S,4R)-1-(tert-butoxycarbonyl)-4-isopropoxypyrrolidine-2-carboxylic acid

A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (Intermediate 9-step 1, 10.0 g, 43.3 mmol) in DMF (100 ml) was treated with sodium hydride (4.15 g, 173 mmol) at 0° C. After stirring about 15 minutes at 0° C., 2-bromopropane (15.9 g, 129.8 mmol) was added and stirred at ambient temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C. then 100 ml water was added slowly over about 30 minutes and stirred at room temperature for about 4 hours. Ethyl acetate (200 ml) was added to the reaction mixture and two layers were separated. The aqueous phase was acidified (pH˜5) with 1N HCl, extracted with ethyl acetate (2×250 ml), washed with brine, dried over Na₂SO₄ and concentrated to afford the title compound (8.2 g, yield: 70%). H¹ NMR (DMSO-D₆, 300 MHz): δ 12.46 (bs, 1H), 4.23 (m 1H), 4.10 (m, 1H), 3.22-3.41 (m, 3H), 2.12 (m, 1H), 1.97 (m, 1H), 1.39 & 1.34 (2s, 9H), 1.34 (t, 6H).

Step 2: Synthesis of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-isopropoxypyrrolidine-1,2-dicarboxylate

To a stirred solution (2S,4R)-1-(tert-butoxycarbonyl)-4-isopropoxypyrrolidine-2-carboxylic acid (step 1, 10.0 g, 36.6 mmol) in DCM (100 ml) at 0° C. was added triethyl amine (11.1 g, 109.9 mmol) and after stirring about 10 minutes, 2-bromo-1-phenylethanone (8.74 g, 43.9 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), water was added to the reaction mixture and extracted with dichloromethane (200 ml). The organic layer was washed with brine solution (100 ml), dried over Na₂SO₄, filtered and was concentrated under reduced pressure to afford the title compound (8.0 g, yield: 56%). The crude product was used in the next step without further purification. H¹ NMR (DMSO-D₆, 300 MHz): δ 7.97 (m, 2H), 7.70 (m, 1H), 7.56 (m, 2H), 5.47-5.59 (m, 2H), 4.36 (m, 1H), 4.21 (m, 1H), 3.64 (m, 1H), 3.47 (m, 1H), 3.28 (m, 1H), 2.26 (m, 2H), 1.39 & 1.36 (2s, 9H), 1.09 (t, 6H).

Step 3: Synthesis of (2S,4R)-tert-butyl 4-isopropoxy-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-isopropoxy pyrrolidine-1,2-dicarboxylate (step 2, 8.0 g, 20.46 mmol) in toluene (100 ml), ammonium acetate (32.23 g, 409.2 mmol) was added at room temperature and resulting reaction mixture was refluxed for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added, extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2×100 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×100 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford the title compound (1.6 g, yield: 21%). H^(t) NMR (CDCl₃, 300 MHz): δ 7.69 (m, 2H), 7.36 (m, 2H), 7.22 (m, 2H), 5.07 (m, 1H), 4.37 (m, 1H), 3.71 (m, 1H), 3.48 (m, 1H), 3.13 (m, 1H), 1.90-2.26 (m, 2H), 1.45 (s, 9H), 1.19 (t, 6H).

Step 4: Synthesis of 2-((2S,4R)-4-isopropoxypyrrolidin-2-yl)-4-phenyl-1H-imidazole TFA salt

To a solution of (2S,4R)-tert-butyl 4-isopropoxy-2-(4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (step 3, 1.65 g, 4.44 mmol) in DCM (20 ml) was added trifluoroacetic acid (10 ml) and stirred at room temperature for about 4 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford the title compound (1.71 g) as a TFA salt. H¹ NMR (DMSO-D₆, 300 MHz): δ 10.0 (broad peak, 1H), 7.90 (s, 1H), 7.75 (m, 2H), 7.53 (m, 1H), 7.45 (m, 2H), 7.32 (m, 1H), 4.95 (m, 1H), 4.50 (m, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 3.33 (m, 1H), 2.35-2.55 (m, 2H), 1.13 (d, 6H).

Intermediate 37: Preparation of 4-tert-butyl-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole TFA salt

Step 1: Synthesis of (2S,4R)-tert-butyl 2-(3,3-dimethyl-2-oxobutylcarbamoyl)-4-(2-methoxy ethoxy)pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy) pyrrolidine-2-carboxylic acid (Intermediate 9-step 2, 10.0 g, 34.72 mmol) in DCM (60 ml) at 0° C. was added DIPEA (23.0 ml, 137.4 mmol) and HATU (16.1 g, 41.23 mmol). After stirring for about 10 minutes, 1-amino-3,3-dimethylbutan-2-one hydrochloride (5.18 g, 34.72 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), water was added to the reaction mixture and extracted with ethyl acetate (2×200 ml) and washed with brine solution. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 55% ethyl acetate/hexane as an eluent to afford the title compound (11.1 g, yield: 84%). H¹ NMR (DMSO-D₆, 300 MHz): δ 8.01 (m, 1H), 4.0-4.21 (m, 4H), 3.3-3.61 (m, 6H), 3.24 (s, 3H), 2.20 (m, 1H), 1.97 (m, 1H), 1.39 & 1.32 (2s, 9H), 1.11 (s, 9H).

Step 2: Synthesis of (2S,4R)-tert-butyl 2-(4-tert-butyl-1H-imidazol-2-yl)-4-(2-methoxyethoxy) pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-tert-butyl 2-(3,3-dimethyl-2-oxobutylcarbamoyl)-4-(2-methoxyethoxy)pyrrolidine-1-carboxylate (step 1, 11.50 g, 29.87 mmol) in xylene (200 ml), ammonium acetate (45.90 g, 597.4 mmol) was added at room temperature and resulting mixture was heated to 130° C. for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, aqueous NaHCO₃ solution was added, extracted with ethyl acetate (2×200 ml) and the organic layer was washed with 1N HCl (2×100 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×250 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (3.10 g, yield: 29%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.37 (bs, 1H), 6.56 (broad peak, 1H), 4.63-4.98 (m, 1H), 4.12 (m, 1H), 3.43-3.60 (m, 6H), 3.25 (s, 3H), 2.25 (m, 1H), 2.08 (m, 1H), 1.38 & 1.20 (2s, 9H), 1.11 (s, 9H).

Step 3: Synthesis of 4-tert-butyl-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole TFA salt

To a solution of (2S,4R)-tert-butyl 2-(4-tert-butyl-1H-imidazol-2-yl)-4-(2-methoxy ethoxy)pyrrolidine-1-carboxylate (step 2, 3.0 g, 8.19 mmol) in DCM (30 ml) was added trifluoroacetic acid (15 ml) and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford title compound as a TFA salt (3.1 g). H¹ NMR (DMSO-D₆, 300 MHz): δ 13.85 (broad peak, 1H), 11.30 (broad peak, 1H), 7.30 & 7.23 (2s, 1H), 5.06 (m, 1H), 4.43 (m, 1H), 3.3-3.60 (m, 6H), 3.26 (s, 3H), 2.3-2.60 (m, 2H), 1.29 (s, 9H).

Intermediate 38: Preparation of 2-(2S,4R)-4-methoxypyrrolidin-2-yl)-4-phenyl-1H-imidazole TFA salt

Step 1: Synthesis of (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid

A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (Intermediate 9-step 1, 25.0 g, 108.20 mmol) in DMF (250 ml) was treated with sodium hydride (10.38 g, 432.90 mmol) at 0° C. After stirring about 10 minutes 0° C., methyl iodide (46.10 g, 324.60 mmol) was added and stirred at ambient temperature for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C. then 200 ml water was added slowly over 30 minutes and stirred at room temperature for about 4-5 hours. Ethyl acetate (200 ml) was added to the reaction mixture and two layers were separated. The aqueous phase was acidified (pH˜5) with 2N HCl, extracted with ethyl acetate (2×350 ml), washed with brine, dried over Na₂SO₄ and concentrated to afford the title compound (14.20 g, yield: 54%). H¹ NMR (DMSO-D₆, 300 MHz): δ 12.55 (bs, 1H), 4.06 (m, 1H), 3.95 (m, 1H), 3.39 (m, 1H), 3.32 (m, 1H), 3.21 (s, 3H), 2.30 (m, 1H), 1.95 (m, 1H), 1.39 & 1.34 (2s, 9H).

Step 2: Synthesis of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-methoxypyrrolidine-1,2-dicarboxylate

To a stirred solution (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (step 1, 6.0 g, 24.48 mmol) in DCM (80 ml) at 0 C was added DIPEA (8.49 ml, 48.97 mmol) and after stirring about 10 minutes, 2-bromo-1-phenylethanone (5.36 g, 26.93 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with dichloromethane (200 ml), washed with water (200 ml), saturated brine (100 ml), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified on silica gel column (100-200 mesh, eluted in 20-25% ethyl acetate/hexane) to afford the title compound (6.80 g, yield: 77%). H¹ NMR (CDCl₃, 300 MHz): δ 7.91 (m, 2H), 7.60 (m, 1H), 7.49 (m, 2H), 5.20-5.60 (m, 2H), 4.52 (m, 1H), 4.11 (m, 1H), 3.63 (m, 1H), 3.53 (m, 1H), 3.35 (s, 3H), 2.43 (m, 2H), 1.46 & 1.43 (2s, 9H).

Step 3: Synthesis of (2S,4R)-tert-butyl 4-methoxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-oxo-2-phenylethyl) 4-methoxy pyrrolidine-1,2-dicarboxylate (step 2, 6.80 g, 18.83 mmol) in toluene (80 ml), ammonium acetate (15.90 g, 207.20 mmol) was added at room temperature and resulting reaction mixture was refluxed for about 28 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate (200 ml) and the organic layer was washed with 1N HCl (2×100 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×100 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford the title compound (4.65 g, yield: 72%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.92 (bs, 1H), 7.72 (m, 2H), 7.48 (s, 1H), 7.31 (m, 2H), 7.14 (m, 1H), 4.75 (m, 1H), 4.04 (m, 1H), 3.57 (m, 2H), 3.26 (s, 3H), 2.32 (m, 1H), 2.06 (m, 1H), 1.38 & 1.11 (2s, 9H).

Step 4: Synthesis of 2-((2S,4R)-4-methoxypyrrolidin-2-yl)-4-phenyl-1H-imidazole TFA salt

To a solution of (2S,4R)-tert-butyl 4-methoxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 3, 4.65 g, 13.55 mmol) in DCM (50 ml) was added trifluoroacetic acid (10.3 ml, 135.5 mmol) and stirred at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford the title compound (4.6 g) as a TFA salt. H¹ NMR (DMSO-D₆, 300 MHz): δ 10.04 (broad peak, 1H), 7.88 (s, 1H), 7.83 (m, 2H), 7.44 (m, 2H), 7.31 (m, 1H), 4.93 (m, 1H), 4.29 (m, 1H), 3.4-3.55 (m, 2H), 3.31 (s, 3H), 2.65 (m, 1H), 2.39 (m, 2H).

Intermediate 39: Preparation of 4-(3-fluorophenyl)-2-((2S,4R)-4-methoxypyrrolidin-2-yl)-1H-imidazole TFA salt

Step 1: Synthesis of (2S,4R)-1-tert-butyl 2-(2-(3-fluorophenyl)-2-oxoethyl) 4-methoxy pyrrolidine-1,2-dicarboxylate

To a stirred solution (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (Intermediate 38-step 1, 3.85 g, 15.7 mmol) in DCM (40 ml) at 0° C. was added DIPEA (8.16 ml, 47.17 mmol) and after stirring about 10 minutes, 2-bromo-1-(3-fluorophenyl)ethanone (Intermediate 2-step 1, 4.09 g, 18.85 mmol) was added and the reaction mixture was allowed to stir at room temperature for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with dichloromethane (200 ml) and washed with water (200 ml), saturated brine (100 ml), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified on silica gel column (100-200 mesh, eluted in 25% ethyl acetate/hexanes) to afford the title compound (1.8 g, yield: 30%). H^(t) NMR (DMSO-D₆, 300 MHz): δ 7.82 (m, 2H), 7.61 (m, 2H), 5.56 (ABq, 2H), 4.32 (m, 1H), 4.01 (m, 1H), 3.44 (m, 2H), 3.31 (s, 3H), 2.43 (m, 1H), 2.23 (m, 1H), 1.39 & 1.36 (2s, 9H).

Step 2: Synthesis of (2S,4R)-tert-butyl 2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-methoxy pyrrolidine-1-carboxylate

To a stirred solution of (2S,4R)-1-tert-butyl 2-(2-(3-fluorophenyl)-2-oxoethyl) 4-methoxy pyrrolidine-1,2-dicarboxylate (step 1, 1.80 g, 4.73 mmol) in toluene (30 ml), ammonium acetate (3.78 g, 47.36 mmol) was added at room temperature and resulting reaction mixture was refluxed for about 18 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, aqueous NaHCO₃ solution was added, extracted with ethyl acetate (2×00 ml) and the organic layer was washed with 1N HCl (2×100 ml). Aqueous layer was basified with 2N NaOH (pH˜8 to 9), the product was extracted with ethyl acetate (2×100 ml), washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (1.21 g, yield: 71%). H¹ NMR (DMSO-D₆, 300 MHz): δ 12.03 (bs, 1H), 7.48-7.60 (m, 3H), 7.33 (m, 1H), 6.93 (m, 1H), 4.76 (m, 1H), 4.04 (m, 1H), 3.57 (m, 2H), 3.25 (s, 3H), 2.35 (m, 1H), 2.07 (m, 1H), 1.39 & 1.11 (2s, 9H).

Step 3: Synthesis of 4-(3-fluorophenyl)-2-((2S,4R)-4-methoxypyrrolidin-2-yl)-1H-imidazole TFA salt

To a solution of ((2S,4R)-tert-butyl 2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-methoxy pyrrolidine-1-carboxylate (step 2, 1.21 g, 3.36 mmol) in DCM (20 ml) was added trifluoroacetic acid (8 ml) and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford title compound (1.2 g) as a TFA salt. H¹ NMR (DMSO-Ds, 300 MHz): δ 10.05 (broad peak, 1H), 7.89 (s, 1H), 7.62 (m, 2H), 7.43 (m, 1H), 7.08 (m, 1H), 4.85 (m, 1H), 4.29 (m, 1H), 3.38-3.50 (m, 2H), 3.31 (s, 3H), 2.35-2.60 (m, 2H).

Intermediate 40: Preparation of ((S)-4,5-dimethyl-2-(pyrrolidin-2-yl)-H-imidazole TFA salt

Step 1: Synthesis of (S)-tert-butyl 2-(4,5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (Intermediate 30-step 2, 3.0 g, 15.07 mmol) in toluene (30 ml) was added 2,3-butanedione (1.29 g, 15.07 mmol), ammonium acetate (12.76 g, 165.8 mmol) and acetic acid (0.2 ml). The resulting reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, aq NaHCO₃ solution was added, extracted with ethyl acetate (2×100 ml), combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to afford title compound (3.72 g, yield: 93%). H¹ NMR (DMSO-D₆, 300 MHz): δ 11.16 (broad s, 1H), 4.59 (m, 1H), 3.27-3.42 (m, 2H), 1.78-2.10 (m, 4H), 1.98 (s, 6H), 1.39 & 1.17 (2s, 9H).

Step 2: Synthesis of ((S)-4, 5-dimethyl-2-(pyrrolidin-2-yl)-1H-imidazole TFA salt

To a solution of (S)-tert-butyl 2-(4,5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 1, 3.70 g, 14.01 mmol) in DCM (40 ml) was added trifluoroacetic acid (20 ml) and stirred at room temperature for about 5 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford title compound (3.80 g) as a TFA salt. H¹ NMR (DMSO-D₆, 300 MHz): δ 9.90 (broad peak, 1H), 4.94 (m, 1H), 3.37 (m, 2H), 2.14-2.32 (m, 2H), 2.23 (s, 6H), 1.96-2.05 (m, 2H).

Intermediate 41: Preparation of (S)-2-(pyrrolidin-2-yl-1H-imidazole TFA salt

Step 1: Synthesis of (S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a stirred solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (Intermediate 30-step 2, 5.0 g, 25.2 mmol) in toluene (50 ml) was added glyoxal (1.46 g, 25.2 mmol), ammonium acetate (2.14 g, 27.7 mmol) and acetic acid (0.3 ml). The resulting solution was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, aqueous NaHCO₃ solution was added and extracted with ethyl acetate (2×100 mil), combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified on silica gel column (100-200 mesh, eluted in 90-100% ethyl acetate/hexane) to afford the title compound (1.40 g, yield: 23%). H¹ NMR (DMSO-D₆, 300 MHz): δ 12.65 & 11.62 (2 bs, 1H), 6.86 (bs, 2H), 4.65-4.79 (m, 1H), 3.3-3.47 (m, 2H), 1.78-2.10 (m, 4H), 1.39 & 1.17 (2s, 9H).

Step 2: Synthesis of (S)-2-(pyrrolidin-2-yl)-1H-imidazole TFA salt

To a solution of (S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate (step 1, 1.40 g, 5.93 mmol) in DCM (20 ml) was added trifluoroacetic acid (10 ml) and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvents were evaporated under reduced pressure to afford title compound (1.27 g, yield: 85%) as a TFA salt which was used in the next reaction without further purification. Mass (ESI): 138.23 (M+H)⁺.

EXAMPLES Example 1: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR, 13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid

Step 1: Synthesis of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate

To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (Prepared as described in J. Med. Chem. 2009, 52, 3248-3258, 3.8 g, 7.63 mmol) in DCM (35 ml), Oxalyl chloride (2.7 ml, 21.2 mmol) in DCM (4 ml) was added 1 drop DMF at 0° C. and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to the above stirred solution of (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine (Intermediate 1, 1.7 g, 7.94 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water followed by 1N HCl, water, brine and dried over Na₂SO₄. The solvent was evaporated and purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (2.8 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.79-0.98 (m, 13H), 1.00-1.03 (m, 7H), 1.18-1.56 (m, 16H), 160-1.99 (m, 11H), 2.09 (s, 3H), 2.10-2.95 (m, 6H), 3.02-3.74 (m, 2H), 4.45-4.50 (m, 1H), 4.61-4.75 (m, 1H), 4.77 (s, 1H), 5.33 (m, 1H), 7.24-7.29 (m, 2H), 8.05-8.07 (d, 1H), 8.43-8.44 (d, H), 8.97 (s, 1); Mass: 694 [M+1]⁺695(100%).

Step 2: Synthesis of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)methanone

To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (step 1, 2.8 g, 4.06 mmol) in methanol (30 ml) was added potassium carbonate (4.4 g, 32 mmol) at room temperature and stirred for about 16 hours. After completion of the reaction (monitored by TLC), the volatile components were evaporated. The aqueous layer was extracted with ethyl acetate, organic layer was washed with water, brine and dried over Na₂SO₄. The solvent was evaporated and the resulting crude was purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (Wt: 1.8 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.68-0.99 (m, 9H), 1.01-1.23 (m, 10H), 1.25-1.63 (m, 23H), 1.72-1.99 (m, 3H), 2.28-2.91 (m, 9H), 3.02-75 (m, 3H), 4.60 (s, 1H), 4.77 (s, 1H), 5.30-5.33 (m, 1H), 7.24-7.28 (m, 2H), 8.05-8.07 (d, 1H), 8.42-8.44 (d, 1H), 8.97-8.98 (s, 1H); Mass: 652 [M+1]⁺ 653 (100%).

Step 3: Synthesis of 1-benzyl 3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (1R,3S)-2,2-dimethylcyclobutane-1,3-dicarboxylate

To a stirred solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl(S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)methanone (step 2, 0.6 g, 0.9 mmol, 1.0 eq) in pyridine (10 ml) was added DMAP (0.2 g, 1.8 mmol, 2.0 eq) and (1S,3R)-3-(benzyloxycarbonyl)-2,2-dimethyloyobutanecarboxylic-2,4,6-trichlorobenzoic anhydride (prepared as described in WO 2013/160810 A2, 0.51 g, 1.10 mmol, 1.2 eq). The reaction mixture was heated FOR overnight at 90° C. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure and diluted with water. The aqueous layer was extracted with CH₂Cl₂ (2×50 ml), the DCM layer was washed with 1N HCl, followed by water and brine solution. The organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 1.5% methanol: dichloromethane as an eluent to obtain the title compound (0.5 g) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.77-0.98 (m, 21H), 1.00-1.68 (m, 22H), 1.74-1.98 (m, 8H), 2.01-2.12 (m, 5H), 2.27-231 (m, 2H), 2.61-2.91 (m, 6H), 3.02-3.74 (m, 2H), 4.43-4.45 (m, 1H), 4.61 (s, 10H), 4.75 (s, 1H), 5.11-5.12 (m, 2H), 7.27-7.34 (m, 6H), 8.43-8.45 (s, 1H); Mass: [M+1]⁺ 896 (100%).

Step 4: Synthesis of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclo butane-1-carboxylic acid

To a solution of 1-benzyl 3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b, 8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (1R,3S)-2,2-dimethylcyclobutane-1,3-dicarboxylate (step 3, 0.5 g, 0.55 mmol, 1.0 eq) dissolved in EtOAc:MeOH (1:1), added 0.25 g of Pd/C (Wet: 10%) under N₂ atmosphere and was added (0.17 g, 2.7 mmol) of ammonium acetate at room temperature, stirred for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and was washed with hot EtOAc: MeOH (1:1, 50 ml). The filtrate was evaporated under reduced pressure, diluted with water (10 ml) and extracted with CH₂Cl₂ (2×200 ml). The organic layer was washed with brine solution and dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 6% methanol: dichloromethane as an eluent to afford the title compound (0.065 g) as a white solid. ¹H NMR (300 MHz, DMSO-d6): δ 0.85-0.99 (m, 19H), 1.26-1.49 (m, 17H), 1.54-1.58 (m, 1011H), 1.83-1.89 (m, 4H), 2.07-2.25 (m, 3H), 2.30-2.78 (m, 4H), 2.81 (m, 2H), 3.63-3.78 (m, 1H), 4.16-4.36 (m, 2H), 4.46-4.54 (m, 2H), 5.01-5.30 (m, 2H), 7.12-7.17 (d, 1H), 7.40-7.50 (m, 1H), 7.70-7.7 (m, 2H), 8.43-8.52 (m, 1H); Mass: 806 [M+1]⁺ (100%); HPLC Purity: 92.7%.

The following compounds are prepared as described in the above Example-1 procedure with their corresponding intermediates (S)-5-(3-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 2); (S)-5-(3-fluoro-4-methylphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 3); (S)-3-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine (Intermediate 5); (S)-2-(pyrrolidin-2-yl)-5-(4-(trifluoromethyl)phenyl)-1H-imidazole (Intermediate 6); 2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-4-phenyl-1H-imidazole (Intermediate 9); 4-(3-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 10); 4-(4-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 11); 3-(2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazol-4-yl)pyridine 2,2,2-trifluoroacetate (Intermediate 12); (S)-2-Phenyl-5-(pyrrolidin-2-yl)-1,3,4-oxadiazole (Intermediate 13); (S)-4-tert-butyl-2-(pyrrolidin-2-yl)oxazole (Intermediate 14); (S)-5-methyl-4-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 15); (S)-4-isopropyl-2-(pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 16); (S)-5-phenyl-2-(pyrrolidin-2-yl)oxazole (Intermediate 17); (S)-5-tert-butyl-2-(pyrrolidin-2-yl)oxazole (Intermediate 18); (S)-4-phenyl-2-(pyrrolidin-2-yl)oxazole (Intermediate 19); (S)-4-tert-butyl-2-(pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 20); (S)-5-phenyl-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 21); (S)-5-(4-chlorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 23); (S)-3-(5-phenyl-1H-imidazol-2-yl)piperidin-1-ium chloride (Intermediate 24); (S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-ium chloride (Intermediate 27); (S)-4-(3-fluoro-4-methoxyphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 28); 2,2,2-trifluoro-1-((2S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)-114-pyrrolidin-1-yl)ethan-1-one (Intermediate 30); (S)-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole TFA salt (Intermediate 31); (S)-5-(2,4-difluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 32); (S)-5-(2-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 33); (S)-4-(3-chlorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole TFA salt (Intermediate 34); (3R,5S)-5-(4-phenyl-1H-imidazol-2-yl)pyrrolidin-3-ol TFA salt (Intermediate 35); 2-((2S,4R)-4-isopropoxypyrrolidin-2-yl)-4-phenyl-1H-imidazole TFA salt (Intermediate 36); 4-tert-butyl-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole TFA salt (Intermediate 37); 2-((2S,4R)-4-methoxypyrrolidin-2-yl)-4-phenyl-1H-imidazole TFA salt (Intermediate 38); 4-(3-fluorophenyl)-2-((2S,4R)-4-methoxypyrrolidin-2-yl)-1H-imidazole TFA salt (Intermediate 39); ((S)-4,5-dimethyl-2-(pyrrolidin-2-yl)-1H-imidazole TFA salt (Intermediate 40); (S)-2-(pyrrolidin-2-yl)-1H-imidazole TFA salt (Intermediate 41); (1R,3S,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (Commercially available), to give the corresponding following compounds:

Example 2: Preparation of (1R,3S)-3-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.84-0.98 (m, 21H), 1.00-1.14 (s, 19H), 1.29-1.56 (m, 4H), 1.59-1.82 (m, 4H), 2.09-2.18 (m, 7H), 2.23-2.8 (m, 6H), 2.92-3.05 (m, 3H), 3.52-4.13 (m, 3H), 4.20-4.24 (m, 1H), 4.61 (s, 1H), 4.77 (s, 1H), 5.31-5.35 (m, 1H), 7.12-7.17 (m, 2H), 7.38-7.45 (m, 1H), 10.50 (s, 1H); Mass: 836 [M+1]⁺ 837 (100%); HPLC Purity: 93.20%.

Example 3: Preparation of (1R,3S)-2,2-dimethyl-3(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl) 3a-((S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.85-0.99 (m, 19H), 1.26-1.49 (m, 17H), 1.54-1.58 (m, 10H), 1.83-1.89 (m, 4H), 2.07-2.25 (m, 3H), 2.30-2.78 (m, 4H), 2.81 (m, 2H), 3.63-3.78 (m, 1H), 4.16-4.36 (m, 2H), 4.46-4.54 (m, 2H), 5.01-5.30 (m, 2H), 7.12-7.17 (d, 1H), 7.40-7.50 (m, 1H), 7.70-7.7 (m, 2H), 8.43-8.52 (m, 1H); Mass: 806 [M+1]+(100%); HPLC Purity:

Example 4: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.84-0.98 (m, 21H), 1.00-1.14 (s, 19H), 1.29-1.56 (m, 4H), 1.59-1.82 (m, 4H), 2.09-2.18 (m, 7H), 2.23-2.8 (m, 6H), 2.92-3.05 (m, 3H), 3.52-4.13 (m, 3H), 4.20-4.24 (m, 1H), 4.61 (s, 1H), 4.77 (s, 1H), 5.31-5.35 (m, 1H), 7.01-7.11 (m, 3H), 7.12-7.13 (m, 2H), 10.50 (s, 1H); Mass: 823 [M+l]+824 (100%); HPLC Purity: 93%.

Example 5: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S-2-(5-(4-ethoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.08-0.91 (m, 0.12-1.28 (m, 5H), 1.37-1.39 (m, 34H), 1.50-1.58 (m, 15H), 1.82-1.89 (m, 4H), 2.33-2.39 (m, 2H), 2.71-2.78 (m, 3H), 3.01-3.13 (m, 1H), 3.57-3.57 (s, 1K), 3.64-3.66 (d, 1H), 4.0-4.14 (m, 3H), 4.36-4.37 (m, 11H), 4.56 (s, 1H), 4.6 (s, 1H), 5.02-5.04 (m, 1H), 6.84-6.87 (d, 2H), 7.28 (m, 1H), 7.59-7.62 (m, 2H), 7.62-7.70 (m, 2K), 10.50 (s, 1H); Mass: 849 [M+1]⁺; HPLC Purity: 97.43%.

Example 6: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(4-(trifluoromethyl) phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl cyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.84-0.98 (m, 21H), 1.00-1.14 (s, 19H), 1.29-1.56 (m, 4H), 1.59-1.82 (m, 4H), 2.09-2.18 (m, 7H), 2.23-2.8 (m, 6H), 2.92-3.05 (m, 3H), 3.52-4.13 (m, 3H), 4.20-4.24 (m, 1H), 4.61 (s, 1H), 4.77 (s, 1H), 5.31-5.35 (m, 1H), 7.01-7.11 (m, 3H), 7.12-7.13 (m, 2H),) 10.50 (s, 1H); Mass: 873 [M+1]⁺874 (100%); HPLC Purity: 90.84%.

Example 7: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11R,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy)-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.13 (bs, 1H), 11.65 (bs, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.44 (s, 1H), 7.29 (t, J=8.0 Hz, 2H), 7.13 (t, J=8.0, 1H), 5.13 (m, 1H), 4.55 (s, 1U), 4.46 (s, 1H), 4.33 (m, 2H), 3.78 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.95 (m, 1H), 2.75 (m, 2H), 2.15 (m, 4H), 0.70-2.0 (m, 48H); Mass (ESI): 880.57 [M+H]⁺; HPLC: 94.83%.

Example 8: Preparation of (1R,3S)-3-((((R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.15 (bs, 1H), 11.76 (bs, 1H), 7.45-7.60 (m, 3H), 7.34 (m, 1H), 6.94 (m, 1H), 5.13 (m, 11H), 4.54 (s, 1H), 4.47 (s, 1H), 4.33 (m, 2H), 3.80 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.7-3.0 (m, 3H), 2.1-2.35 (m, 41H), 0.70-2.0 (m, 48H); Mass (ESI): 898.69 (M+H); HPLC: 92.90%.

Example 9: Preparation of (1R,3S)-3-((((R,3aS,5aR,5bR,7a,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-di ethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 11.67 (bs, 1H), 7.72 (m, 2H), 7.42 (s, 1H), 7.13 (t, J=9.6 Hz, 2H), 5.12 (m, 1H), 4.55 (s, 1H), 4.47 (s, 1H), 4.31 (m, 2H), 3.82 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.7-3.0 (m, 3H), 2.05-2.40 (m, 4H), 0.70-2.0 (m, 48H); Mass (ESI): 898.19 [M+H]⁺; HPLC: 94.56%.

Example 10: Preparation of (1R,3 S-3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S 4R)-4-(2-methoxyethoxy)-2-(4-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.11 (bs, 1H), δ 11.80 (bs, 1H), 8.93 (s, 1H), 8.33 (d, J=4.8 Hz, 1H), 8.04 (d, J=8.6, 1H), 7.59 (s, 1H), 7.33 (dd, J=8.6, 4.6 Hz, 1H), 5.13 (m, 1H), 4.54 (s, 1H), 4.47 (s, 1H), 4.30 (m, 2H), 3.82 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 31H), 2.7-3.0 (m, 3H), 2.05-2.40 (m, 4H), 0.70-2.0 (m, 48H); Mass (ESI): 881.66 (M+H); HPLC: 85.42%.

Example 11: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl) cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.17 (s, 1H), 7.95 (d, J=7.5 Hz, 2H), 7.59 (m, 3H), 5.20 (m, 1H), 4.52 (s, 1H), 4.46 (s, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.65 (m, 1H), 2.6-2.75 (m, 2H), 2.10-2.50 (m, 7H), 0.70-2.0 (m, 481H); Mass (ESI): 808.09 [M+H]⁺; HPLC: 92.27%.

Example 12: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)oxazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxycarbonyl)-2,2-dimethylyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.10 (bs, 1H), 7.56 (s, 1H), 4.96 (m, 1H), 4.56 (s, 1H), 4.49 (s, 1H), 4.30 (m, 1H), 3.75 (m, 1H), 3.60 (m, 1H), 2.80-3.0 (m, 21H), 2.10-2.60 (m, 5H), 0.70-2.0 (m, 59H); Mass (ESI): 787.59 [M+H]⁺; HPLC: 90.08%.

Example 13: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11a,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-methyl-4-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.11 (bs, 11H), 11.40 (bs, 1H), 7.57 (d, J=7.5 Hz, 2H), 7.31 (t, 3=8.3 Hz, 2H), 7.15 (t, J=7.5, 1H), 5.01 (m, 1H), 4.57 (s, 1H), 4.48 (s, 1H), 4.33 (m, 1H), 3.75 (m, 1H), 3.62 (m, 1H), 2.90 (m, 2H), 2.80 (m, 2H), 2.34 (s, 3H), 2.10-2.60 (m, 5H), 0.70-2.0 (m, 48H); Mass (ESI): 820.52 [M+H]⁺; HPLC: 96.41%.

Example 14: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-isopropyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.15 (s, 1H), 11.0 (br peak, 1H), 6.53 (s, 1H), 5.0 (m, 11H), 4.55 (s, 1H), 4.49 (s, 1H), 4.32 (m, 1H), 3.78 (m, 1H), 3.62 (m, 1H), 2.75-3.0 (m, 3H), 2.10-2.60 (m, 6H), 0.60-2.0 (m, 55H); Mass (ESI): 772.68 [M+H]⁺; HPLC: 89.24%.

Example 15: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyloxazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.14 (bs, 1H), δ 7.65 (d, J=8.0 Hz, 2H), 7.54 (s, 1H), 7.44 (t, J=8.0 Hz, 2H), 7.33 (t, J=8.0 Hz, 1H), 5.08 (m, 1H), 4.53 (s, 1H), 4.46 (s, 1H), 4.32 (m, 1H), 3.85 (m, 1H), 3.64 (m, 1H), 2.6-2.82 (m, 3H), 2.15-2.40 (m, 4H), 0.70-2.0 (m, 50H); Mass (ESI): 807.55 [M+H]⁺; HPLC: 96.78%.

Example 16: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(tert-butyloxazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.18 (bs, 1H), 6.65 (s, 1H), 4.96 (m, 1H), 4.56 (s, 1H), 4.49 (s, 1H), 4.33 (m, 1H), 3.61-3.72 (m, 2H), 2.75 (m, 3H), 2.10-2.60 (m, 4H), 0.70-2.0 (m, 59H); Mass (ESI): 787.59 [M+H]⁺; HPLC: 94.09%.

Example 17: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(4-phenyloxazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.14 (bs, 1H), 8.44 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.40 (t, J=8.0 Hz, 2H), 7.29 (t, J=8.0 Hz, 1H), 5.05 (m, 1H), 4.54 (s, 1H), 4.46 (s, 1H), 4.33 (m, 1H), 3.84 (m, 1H), 3.64 (m, 1H), 2.6-2.82 (m, 3H), 2.15-2.40 (m, 4H), 0.70-2.0 (m, 50H); Mass (ESI): 807.68 [M+H]⁺; HPLC: 93.74%.

Example 18: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.18 (s, 1H), 11.04 (br peak, 1H), 6.54 & 6.35 (bs, 1H), 5.0 (m, 1H), 4.56 (s, 1H), 4.48 (s, 1H), 4.33 (m, 1H), 3.50-3.75 (m, 2H), 2.75-3.0 (m, 3H), 2.10-2.60 (m, 6H), 0.60-2.0 (m, 57H); Mass (ESI): 786.72 [M+H]⁺; HPLC: 90.94%.

Example 19: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-d₆, 300 MHz): δ 12.14 (bs, 1H), 11.68 (s, 1H), 7.74 (d, 2H), 7.48 (s, 1H), 7.36 (d, 2H), 5.05 (d, 1H), 4.54 (d, 2H), 4.33 (t, 1H), 3.78 (s, 1H), 3.60 (s, 1H), 2.81 (q, 2H), 2.23-2.03 (m, 4H), 1.91-1.82 (m, 4H), 1.58-1.39 (m, 10H), 1.32-1.19 (m, 10H), 1.17 (t, 4H), 0.93-0.90 (m, 11H) and 0.87 (s, 11H); Mass: [M]⁺ 840.55 (100%); HPLC: 89.57%.

Example 20: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO): δ 12.14 (s, 1H), 11.91 (s, 1H), 7.73 (d, J=7.5 Hz, 2H), 7.49 (s, 1H), 7.31 (t, J=7.8 Hz, 2H), 7.17-7.12 (m, 1H), 4.65 (s, 1H), 4.53 (s, 1H), 4.35-4.3 (m, 2H), 2.93-2.72 (m, 5H), 2.36-2.24 (m, 21H), 2.21-2.04 (m, 3H), 2.02-1.74 (m, 5H), 1.72-1.21 (m, 23H), 1.69-1.06 (m, 3H), 0.98-0.8 (m, 21H); ES Mass: [M+H]⁺ 820.59.

Example 21: Preparation of (1R,3R)-2,2-dimeth-3-(2-oxo-2-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13a 13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) ethyl)cyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO): δ 11.98 (bs, 1H), 11.6 (bs, 1H), 7.71 (d, J=7.5 Hz, 2H), 7.41 (bs, 1H), 7.33-7.26 (m, 2H), 7.18-7.08 (m, 1H), 5.07 (bs, 1H), 4.54 (s, 1H), 4.46 (s, 1H), 4.39-4.31 (m, 1H), 3.82-3.74 (m, 1H), 3.64-3.58 (m, 1H), 2.83-2.61 (m, 4H), 2.39-2.04 (m, 8H), 1.98-1.71 (m, 4H), 1.63-1.03 (m, 22H), 0.99-0.73 (m, 21H); ES Mass: [M+1]⁺ 820.71; HPLC: 90.03%.

Example 22: Preparation of 2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8, a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)-icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclopropane-1-carboxylic acid

¹H NMR (300 MHz, CDCl₃): δ 0.81-0.91 (m, 6H), 1.03-0.98 (m, 6H), 1.62-1.25 (m, 14H), 1.74-1.69 (m, 6H), 1.94-1.92 (m, 6H), 2.01-1.95 (m, 8H), 2.11-2.08 (m, 6H), 2.28-2.24 (m, 2H), 2.90-2.87 (m, 3H), 3.05-2.99 (m, 2H), 3.74-3.64 (m, 1H), 4.51 (s, 1H), 4.62 (s, 1H), 5.46-5.44 (m, 1H), 7.35-7.33 (m, 1H), 7.44-7.40 (m, 3H), 7.55-7.53 (m, 2H), 10.50 (s, 1H); Mass: 792.51 [M+1]⁺ 794; HPLC purity: 89.2%.

Example 23: Preparation of 2-methyl-2-(4-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a 5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl) phenoxy)propanoicacid

¹H NMR (300 MHz, CDCl₃): δ ppm 11.38 (brs, 0.5H), 7.97 (d, 2H, J=9.0 Hz), 7.50-7.40 (m, 2H), 7.40-7.30 (i, 3H), 7.25-7.20 (m, 1H), 6.98 (d, 2H, J=9.0 Hz), 5.29 (d, 1H, J=7.5 Hz), 4.85-4.80 (m, 1H), 4.81 (s, 1H), 4.77 (s, 1H), 3.45-3.30 (m, 2H), 3.20-3.10 (m, 1H), 2.90-0.75 (m, 52H); ESI MS: [M+H]⁺ 858 (100%); HPLC: 97.5%.

Example 24: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl) cyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO): δ 13.62 (s, 1H), 12.14 (s, 1H), 7.95 (d, J=7.2 Hz, 2H), 7.7 (bs, 1H), 7.48-7.36 (m, 2H), 5.12 (bs, 1H), 4.53 (s, 1H), 4.45 (s, 1H), 4.35-4.3 (m, 1H), 4.14-4.12 (m, 1H), 3.84-3.59 (m, 2H), 2.81-2.63 (m, 2H), 2.54-2.18 (m, 4H), 1.92-1.74 (m, 41H), 1.64-1.28 (m, 19H), 1.27-1.08 (m, 6H), 0.95-0.8 (m, 21H); ES Mass: [M+1]⁺807.48.

Example 25: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(3-fluoro-4-methoxyphenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl-5a,5b,8, 8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 11.61 (bs, 11H), 7.51 (m, 2H), 7.38 (s, 1H), 7.15 (t, J=7.5 Hz, 1H), 5.03 (m, 1H), 4.54 (s, 1H), 4.46 (s, 1H), 4.33 (m, 1H), 3.82 (s, 3H), 3.75 (m, 1H), 3.62 (m, 1H), 2.80-3.0 (m, 4H), 2.10-2.60 (m, 5H), 0.70-2.0 (m, 481); Mass (ESI): 854.65 [M+H]J; HPLC: 92.63%.

Example 26: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(2,4-difluorophenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbon-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.79-0.93 (m, 8H), 0.93 (6H), 1.07-1.26 (m, 101), 1.29-1.56 (m, 12H), 1.69-1.99 (m, 8H), 2.09-2.18 (m, 4H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 5H), 4.20-4.24 (m, 1H), 4.61-4.75 (m, 1H), 4.77 (s, 1H), 4.80 (s, 1H), 5.31-5.35 (m, 1H), 7.01-7.11 (m, 3H), 7.12-7.13 (m, 2H), 7.22-7.70 (m, 3H), 10.50 (s, 1H); Mass: 841 [M+1]⁺ 842 (100%); HPLC Purity: 91.25%.

Example 27: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(2-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.79-0.93 (m, 8H), 0.93 (6H), 1.07-1.26 (m, 10H), 1.29-1.56 (m, 12H), 1.69-1.99 (m, 8H), 2.09-2.18 (m, 4H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 5H), 4.20-4.24 (m, 1H), 4.61-4.75 (m, 1H), 4.77 (s, 1H), 4.80 (s, 1H), 5.31-5.35 (m, 1H), 7.01-7.11 (m, 3H), 7.12-7.13 (m, 2H), 7.22-7.70 (m, 3H), 10.50 (s, 1H); Mass: 823 [M+1]⁺ 824 (100%); HPLC Purity: 87.28%.

Example 28: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(3-chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl-5a 5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.14 (bs, 1H), 11.73 (bs, 1H), 7.75 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.56 (s, 1H), 7.32 (t, J=8.6 Hz, 1H), 7.18 (m, 1H), 5.03 (m, 1H), 4.54 (s, 1H), 4.46 (s, 1H), 4.32 (m, 1H), 3.80 (m, 1H), 3.63 (m, 1H), 2.70-2.95 (m, 31H), 2.0-2.35 (m, 4H), 0.70-2.0 (m, 50H); Mass (ESI): 840.61 [M+H]⁺; HPLC: 92.06%.

Example 29: Preparation of (R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-hydroxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(pro-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxycarbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.13 (bs, 1H), 11.63 (bs, 1H), 7.70 (m, 2H), 7.43 (s, 1H), 7.29 (m, 2H), 7.13 (m, 1H), 5.11 (m, 1H), 5.07 (m, 1H), 4.55 (s, 1H), 4.46 (s, overlapped, 1H), 4.46 (m, 1H), 4.33 (m, 1H), 3.74 (m, 1H), 3.65 (m, H), 2.70-3.0 (m, 3H), 2.0-2.40 (m, 4H), 0.70-2.0 (m, 48H); Mass (ESI): 822.65 [M+H]⁺; HPLC: 91.41%.

Example 30: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(2S,4R)-4-isopropoxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.13 (bs, 1H), 11.62 (bs, 1H), 7.71 (m, 2H), 7.43 (s, 11H), 7.30 (m, 2H), 7.13 (m, 1H), 5.12 (m, 1H), 4.55 (s, 1H), 4.47 (s, 1H), 4.30-4.44 (m, 2H), 3.6-3.74 (m, 3H), 2.60-2.95 (m, 4H), 1.90-2.40 (m, 5H), 0.70-1.65 (m, 52H); Mass (ESI): 864.70 [M+H]⁺; HPLC: 88.67%.

Example 31: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(tert-butyl)-1H-imidazol-2-yl)-4(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.11 (bs, 1H), 11.08 (bs, 1H), 6.57 & 6.37 (2s, 1H), 5.05 (m, 1H), 4.55 (s, 1H), 4.48 (s, 1H), 4.30 (m, 2H), 3.78 (m, 1H), 3.65 (m, 1H), 3.38 (m, 4H), 3.24 (s, 3H), 2.70-2.95 (m, 3H), 2.0-2.50 (m, 4H), 0.70-2.0 (m, 57H); Mass (ESI): 860.71 (M+H); HPLC: 90.06%.

Example 32: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-methoxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,811a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.14 (bs, 1H), 11.67 (bs, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.44 (s, 1H), 7.30 (t, J=8.0 Hz, 2H), 7.13 (m, 1H), 5.11 (m, 1H), 4.54 (s, 1H), 4.46 (s, 1H), 4.33 (m, 1H), 4.17 (m, 1H), 3.78 (m, 2H), 3.27 (s, 3H), 2.95 (m, 1H), 2.75 (m, 2H), 2.15 (m, 4H), 0.70-2.0 (m, 48H); Mass (ESI): 836.62 [M+H]⁺; HPLC: 93.40%.

Example 33: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-methoxypyrrolidine-1-carbonyl)-5a 5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.15 (bs, 1H), 11.77 (bs, 1H), 7.4-7.60 (m, 3H), 7.32 (m, 1H), 6.94 (m, 1H), 5.10 (m, 1H), 4.46 (s, 1H), 4.33 (m, 1H), 4.16 (m, 1H), 3.80 (m, 2H), 3.27 (s, 3H), 2.70-2.95 (m, 3H), 2.15 (s, 4H), 0.70-2.0 (m, 48H); Mass (ESI): 854.59 [M+H]⁺; HPLC: 96.45%.

Example 34: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-55b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidin-1-carbonyl)-icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid

H^(L) NMR (DMSO-D₆, 300 MHz): δ 0.80-0.92 (m, 18H), 1.06-1.26 (m, 6H), 1.31-1.45 (m, 12H), 1.49-1.77 (m, 9H), 1.82-1.91 (m, 4H), 2.10 (m, 4H), 2.30-2.34 (m, 11H), 2.63 (m, 1H), 2.75-2.81 (m, 2H), 3.37-3.41 (m, 1H), 3.57-3.60 (m, 1H) 3.75 (m, 1H), 4.30-4.35 (s, 1H), 4.48 (s, 11H), 4.55 (s, 1H), 4.99-5.01 (m, 1H), 7.55 (s, 1H), 12.14-12.23 (s, 1H); Mass: [M]⁺ 798.03 (100%); HPLC:91.79%.

Example 35: Preparation of (1R,3S)-3-(((((1R,3aS,5aR,5bR,7a,9S,11a,11bR,13aR,13bR)-3a-((S)-2-(4, 5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 11.58 (broad peak, 1H), 4.95 (m, 1H), 4.63 (s, 1H), 4.52 (s, 1H), 4.33 (m, 1H), 3.75 (m, 2H), 2.70-2.95 (m, 3H), 2.0-2.35 (m, 4H), 2.01 (s, 6H), 0.70-2.0 (m, 50H). Mass (ESI): 758.66 [M+H]⁺; HPLC: 93.67%.

Example 36: Preparation of (1R,3S)-3-((((13aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxycarbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.16 (bs, 1H), 11.47 (bs, 1H), 6.90 (s, 11H), 6.71 (s, 1H), 5.05 (m, 1H), 4.58 (s, 1H), 4.49 (s, 1H), 4.33 (m, 1H), 3.60-3.68 (m, 2H), 2.50-2.82 (m, 3H), 0.70-2.30 (m, 54H); Mass (ESI): 730.64 [M+H]⁺; HPLC: 86.87%.

Example 37: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl oxy)carbonyl)-2,2-dimethylcycobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.14 (bs, 1H), 12.01 (bs, 1H), 7.48 (d, J=8.3 Hz, II), 7.41 (d, J=8.3 Hz, 1H), 7.09 (m, 2H), 5.15 (m, 1H), 4.49 (s, 1H), 4.44 (s, 1H), 4.33 (m, 1H), 3.85 (m, 1H), 3.65 (m, 1H), 2.70-2.95 (m, 3H), 2.0-2.35 (m, 4H), 0.70-2.0 (m, 5011); Mass (ESI): 780.67 [M+H]⁺; HPLC: 89.00%.

Example 38: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo(3.2.1 octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ ppm 12.16 (s, 1H), 4.87-4.77 (m, 1H), 4.67 (s, 1H), 4.54 (s, 1H), 4.58-4.40 (m, 2H), 4.39-4.30 (m, 1H), 3.10-3.00 (m, 2H), 2.98-2.70 (m, 4H), 2.37 (s, 3H), 2.32-2.04 (m, 3H), 2.01-1.70 (m, 10H), 1.70-1.48 (m, 11H), 1.45-1.20 (m, 15H), 1.20-1.00 (m, 4H), 0.97 (s, 3H), 0.90 (brs, 6H), 0.82 (m, 9H), 0.80-0.70 (m, 1H); ES MS: [M+H]⁺ 827.5 (100%); IR (KBr) cm⁻¹: 3434, 2949, 2871, 1724, 1627, 1392, 1193 cm⁻¹; HPLC: 94.70%.

Example 39: Preparation of 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid

2,2-Dimethylsuccinic anhydride (0.312 ml, 2.4 mmol) was added to a stirred solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)methanone (Example 1-step 2, 0.45 g, 0.68 mmol), DMAP (0.168 g, 1.37 mmol) in toluene (20 ml) at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water followed by 1N HCl, water and brine solution. The residue was dried over Na₂SO₄, the solvent was evaporated under vacuum and purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (wt: 0.120 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.78-0.93 (m, 12H), 0.93 (s, 9H), 1.15 (m, 2H), 1.32 (m, 9H), 1.46-1.87 (m, 24H), 2.12 (m, 4H), 2.42-2.79 (m, 7H), 3.63-3.77 (m, 2H), 4.36 (m, 1H), 4.61 (m, 1H), 4.77 (s, 1H), 5.06 (m, 1H), 7.14 (s, 1H), 7.50 (s, 1H), 7.76 (d, 2H), 8.44 (s, 1H); Mass: 779 [M+1]⁺ 780 (100%); HPLC Purity: 87.51+8.52 (isomer) %.

The following compounds are prepared as described in the above Example-39 procedure with their corresponding intermediates (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine (Intermediate 1); (S)-5-(3-fluoro-4-methylphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 3); (S)-5-(4-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 7); (S)-3-phenyl-5-(pyrrolidin-2-yl)-1,2,4-oxadiazole (Intermediate 8); 2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-4-phenyl-1H-imidazole (Intermediate 9); 4-(3-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 10); 4-(4-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 11); (S)-5-(4-methoxyphenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 22); (S)-3-(5-phenyl-1H-imidazol-2-yl)piperidin-1-ium chloride (Intermediate 24); (S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidin-1-ium chloride (Intermediate 27); (1R,3S,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (Commercially available), to give the corresponding following compounds:

Example 40: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.84-0.98 (m, 121H), 1.00-1.14 (s, 9H), 1.29-1.56 (m, 24H), 1.59-1.82 (m, 9H), 2.09-2.18 (m, 4H), 2.23-2.8 (m, 5H), 2.85-2.89 (m, 2H), 2.92-3.05 (m, 3H), 3.52-4.13 (m, 2H), 4.20-4.24 (m, 1H), 4.61 (s, 1H), 4.77 (s, 1H), 5.31-5.35 (m, 1H), 7.12-7.17 (m, 2H), 7.38-7.45 (m, 1H), 10.50 (s, 1H); Mass: 811 [M+1]⁺ 812 (100%); HPLC Purity: 89.25%.

Example 41: Preparation of 5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.79-0.93 (m, 8H), 0.93 (s, 6H), 1.07-1.26 (m, 7H), 1.29-1.56 (m, 10H), 1.57-1.59 (m, 6H), 1.69-1.99 (m, 15H), 2.09-2.18 (m, 4H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 5H), 4.20-4.24 (m, 1H), 4.61 (s, 1H), 4.77 (s, 1H), 5.31-5.35 (m, 1H), 7.22-7.60 (m, 3H), 7.70-7.88 (m, 2H), 10.50 (s, 1H); Mass: 811[M+1]⁺ 812 (100%); HPLC Purity: 92.96%.

Example 42: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bS)-1-(1,2-dihydroxypropan-2-yl)-5a,5b,8,8,11a-pentamethyl-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid

H¹ NMR (300 MHz, DMSO-d6): δ 0.79-0.93 (m, 8H), 0.93 (s, 6H), 1.07-1.26 (m, 10H), 1.29-1.56 (m, 12H), 169-1.99 (m, 8H); 2.09-2.18 (m, 4H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 5H), 4.35-4.40 (m, 1H), 5.31-5.35 (m, 1H), 7.56-7.58 (d, 3H), 7.95-7.98 (d, 2H), 12.18 (s, 1H); Mass: 815 [M+1]⁺ 816 (100%); HPLC Purity: 88.38%.

Example 43: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy-2-(4-phenyl-1-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.10 (bs, 1H), 11.65 (bs, 1H), 7.70 (d, J=8.0 Hz, 2H), 7.44 (s, 11H), 7.29 (t, J=8.0 Hz, 2H), 7.13 (t, J=8.0, 1H), 5.13 (m, 1H), 4.55 (s, 1H), 4.46 (s, 1H), 4.33 (m, 2H), 3.78 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.95 (m, 1H), 2.59 (m, 2H), 2.15 (m, 2H), 0.70-2.0 (m, 48H); Mass (ESI): 854.52 [M+H]⁺; HPLC: 87.44%.

Example 44: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.15 (bs, 1H), 11.76 (bs, 1H), 7.47-7.56 (m, 3H), 7.34 (m, 1H), 6.94 (t, J=8.3 Hz, 11H), 5.13 (m, 1H), 4.54 (s, 1H), 4.46 (s, 1H), 4.33 (m, 21H), 3.78 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.95 (m, 1H), 2.59 (m, 2H), 2.15 (m, 2H), 0.70-2.0 (m, 48H); Mass (ESI): 872.62 [M+H]⁺; HPLC: 86.19%.

Example 45: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.09 (bs, 1H), 11.67 (bs, 1H), 7.75 (m, 2H), 7.42 (s, 1H), 7.13 (t, J=9.6 Hz, 2H), 5.13 (m, 1H), 4.55 (s, 1H), 4.46 (s, 1H), 4.33 (m, 2H), 3.78 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.95 (m, 1H), 2.59 (m, 2H), 2.15 (m, 2H), 0.70-2.0 (m, 48H); Mass (ESI): 872.15 [M+H]⁺; HPLC: 93.19%.

Example 46: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.18 (s, 11H), 11.49 (s, 1H), 7.64 (d, 2H), 7.29 (s, 1H), 6.89 (d, 2H), 5.05 (d, 1H), 4.54 (d, 2H), 4.36 (q, 1H), 3.80 (s, 3H), 3.61 (bs, 1H), 2.83-2.62 (m, 2H), 2.38-2.09 (m, 4H), 1.84 (s, 2H), 1.59 (s, 5H), 1.53-1.28 (m, 15H), 1.16 (d, 8H), 0.93 (s, 9H) and 0.83 (d, 11H); Mass: [M]⁺810.61 (100%); HPLC: 84.09%.

Example 47: Preparation of 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid

¹H NMR (300 MHz, CDCl₃): δ 10.83 (s, 1H), 7.72 (bs, 2H), 7.39-7.3 (m, 3H), 7.22-7.13 (m, 1H), 4.75 (s, 1H), 4.6 (s, 1H), 4.48-4.45 (m, 1H), 3.22-3.03 (m, 2H), 3.02-2.54 (m, 4H), 2.51-1.72 (m, 3H), 1.71-1.68 (m, 4H), 1.66-1.41 (m, 6H), 1.4-1.21 (m, 8H), 1.2-1.06 (m, 2H), 0.96-0.71 (m, 21H); ES Mass: [M+H]+ 794.51.

Example 48: Preparation of 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid

¹H NMR (300 MHz, DMSO): δ 13.61 (s, 1H), 12.16 (s, 1H), 7.95 (d, J=6.9 Hz, 2H), 7.56-7.29 (m, 3H), 5.13 (bs, 1H), 4.52 (s, 1H), 4.45 (s, 1H), 4.41-4.38 (m, 1H), 3.91-3.79 (m, 1H), 3.68-3.56 (m, 1H), 2.78-2.6 (m, 2H), 2.45-2.06 (m, 4H), 2.04-1.68 (m, 4H), 1.66-1.21 (m, 19H), 1.2-1.08 (m, 6H), 0.96-0.78 (m, 2H); ES Mass: [M+1]⁺ 781.53.

Example 49: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S 11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

¹H NMR (300 MHz, CDCl₃): δ ppm 5.13-4.95 (m, 1H), 4.74 (s, 1H), 4.70-4.63 (m, 1H), 4.60 (s, 1H), 4.57-4.46 (m, 2H), 3.10-2.83 (m, 3H), 2.64 (m, 2H), 2.49 (s, 3H), 2.30-2.02 (m, 5H), 2.00-1.72 (m, 8H), 1.69 (s, 3H), 1.71-1.50 (m, 7H), 1.49-1.35 (m, 1H), 1.35-1.25 (m, 9H), 1.07-1.02 (m, 1H), 0.98 (s, 3H), 0.96 (s, 3H), 0.95-0.80 (m, 10H), 0.80-0.75 (m, 1H); ESI MS: [M+H]⁺ 801.6 (40%), [M+Na]⁺ 823.7 (50%); IR (KBr) cm⁻¹: 3436, 2946, 2872, 1733, 1729, 1627, 1404 cm⁻¹; HPLC: 88.3%+10.8% (isomers).

Example 50: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,1 aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

Step 1: Synthesis of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate

To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid (prepared as described in WO 2013/160810 A2, 1.37 g, 2.67 mmol) in DCM (20 ml), Oxalyl chloride (0.97 ml, 7.6 mmol) in DCM (10 ml), 1 drop of DMF was added at 0° C. and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (20 ml), which was added to the above stirred solution of (S)-5-(3-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 2, 0.62 g, 2.66 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water followed by 1N HCl and brine solution. The organic layer was dried over Na₂SO₄, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 30% EtOAc in hexane) to afford the title compound (wt: 1.5 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 10H), 1.07-1.26 (m, 9H), 1.29-1.56 (m, 17H), 169-1.99 (m, 9H), 2.09 (s, 3H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 3H), 4.20-4.24 (m, 1H), 5.31-5.35 (m, 1H), 7.00-7.05 (m, 3H), 7.30-7.33 (m, 1H), 7.72-7.75 (d, 1H); Mass: 727[M+1]⁺ 728 (100%).

Step 2: Synthesis of ((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl) ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8, 1a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methanone

To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (step 1, 1.5 g, 2.06 mmol) in MeOH:THF (10:10 ml) was added potassium carbonate (2.8 g, 20.63 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried over Na₂SO₄. Then the solvent was evaporated and the resulting crude was purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (wt: 0.625 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 10H), 1.07-1.26 (m, 9H), 1.29-1.56 (m, 17H), 169-1.99 (m, 9H), 2.09 (s, 3H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 3H), 5.31-5.35 (m, 1H), 7.00-7.05 (m, 3H), 7.30-7.33 (m, 1H), 7.72-7.75 (d, 1H), 10.50 (s, 1H); Mass: 685 [M+1]+686 (100%).

Step 3: Synthesis of 1-benzyl 3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (1R,3S)-2,2-dimethylcyclobutane-1,3-dicarboxylate

To a stirred solution of ((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methanone (step 2, 0.625 g, 0.916 mmol, 1.0 eq) in pyridine (10 ml) was added DMAP (0.335 g, 2.7 mmol, 2.0 eq) and (1S,3R)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutane carboxylic-2,4,6-trichlorobenzoic anhydride (prepared as described in WO 2013/160810 A2, 0.643 g, 1.37 mmol, 1.5 eq). The reaction mixture was heated for overnight at 90° C. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure and diluted with water. The aqueous layer was extracted with CH₂Cl₂ (2×50 ml), the DCM layer was washed with 1N HCl, followed by water and brine solution. The organic layers were dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 1.5% methanol: dichloromethane as an eluent to afford the title compound (wt: 0.3 g) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.84-0.98 (m, 21H), 1.00-1.14 (s, 19H), 1.29-1.56 (m, 4H), 1.59-1.82 (m, 4H), 2.09-2.18 (m, 7H), 2.23-2.8 (m, 6H), 2.92-3.05 (m, 3H), 3.52-4.13 (m, 3H), 4.20-4.24 (m, 1H), 5.31-5.35 (m, 1H), 7.01-7.11 (m, 3H), 7.12-7.13 (m, 2H), 7.22-7.60 (m, 3H), 7.70-7.88 (m, 2H); Mass: 929 [M+1]⁺ 930 (100%).

Step 4: Synthesis of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid

To a solution of 1-benzyl 3-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(l-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (1R,3S)-2,2-dimethylcyclobutane-1,3-dicarboxylate (step 3, 0.3 g, 0.32 mmol, 1.0 eq) dissolved in EtOAc:MeOH (1:1) added 0.25 g of Pd/C (wet: 10%) under N₂ atmosphere and was added ammonium acetate (0.10 g, 1.5 mmol) at room temperature, stirred for about 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and was washed with hot EtOAc: MeOH (1:1, 20 ml). The filtrate was evaporated under reduced pressure, diluted with water (10 ml) and extracted with CH₂Cl₂ (2×200 ml). The organic layer was washed with brine solution and dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 6% methanol: dichloromethane as an eluent to afford the title compound (wt: 0.050 g) as a white solid. ¹H NMR (300 MHz, DMSO-d6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.84-0.98 (m, 21H), 1.00-1.14 (s, 19H), 1.29-1.56 (m, 4H), 1.59-1.82 (m, 4H), 2.09-2.18 (m, 7H), 2.23-2.8 (m, 6H), 2.92-3.05 (m, 3H), 3.52-4.13 (m, 3H), 4.20-4.24 (m, 1H), 5.31-5.35 (m, 1H), 7.01-7.11 (m, 3H), 7.12-7.13 (m, 2H), 10.50 (s, 1H); Mass: 837 [M+1]+838 (100%); HPLC Purity: 96.82%.

The following compounds are prepared as described in the above Example-50 procedure with their corresponding intermediates (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine (Intermediate 1); 2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-4-phenyl-1H-imidazole (Intermediate 9); 4-(3-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 10); 4-(4-fluorophenyl)-2-((2S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 11); (S)-4-tert-butyl-2-(pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 20); 4-(5-phenyl-1H-imidazol-2-yl)piperidine hydrochloride (Intermediate 25); 4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine (Intermediate 26); (S)-3-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine 1-oxide (Intermediate 29); 2,2,2-trifluoro-1-((2S)-2-(5-(trifluoromethyl)-1-imidazol-2-yl)-1λ⁴-pyrrolidin-1-yl)ethan-1-one (Intermediate 30); (1R,3S,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (Commercially available); (S)-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole TFA salt (Intermediate 31), to give the corresponding following compounds:

Example 51: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)cyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 23H), 1.07-1.16 (m, 3H), 1.29-1.56 (m, 20H), 1.69-1.84 (m, 4H), 2.00-2.32 (m, 4H), 2.33-2.35 (m, 2H), 2.77-2.81 (m, 1H), 3.52-3.83 (m, 2H), 4.29-4.37 (m, 1H), 5.01-5.12 (m, 1H), 7.12 (s, 1H), 7.39-7.48 (m, 1H), 7.66-7.79 (m, 2H), 8.40-8.97 (m, 1H), 10.50 (s, 1H); Mass: 821[M+1]⁺822 (100%); HPLC Purity: 91.59%.

Example 52: Preparation of (1R,3S)-3-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 15H), 0.93 (s, 4H), 1.16-1.23 (m, 3H), 1.29-1.32 (m, 17H), 1.35-1.66 (m, 4H), 1.62-1.99 (m, 4H), 2.09-2.18 (m, 3H), 2.23-2.45 (m, 1H), 2.46-2.56 (m, 2H), 2.78-2.82 (m, 1H), 3.6-3.74 (m, 4H), 4.08-4.14 (m, 2H), 4.34-4.37 (m, 1H), 5.02 (s, 1H), 7.22-7.60 (m, 3H), 7.70-7.88 (m, 2H), 10.50 (s, 1H); Mass:895[M+1]⁺, HPLC Purity: 90.07%.

Example 53: Preparation of 3-(2-((S)-1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-((1S,3R)-3-carboxy-2,2-dimethylcyclobutane-1-carbonyloxy)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine 1-oxide

¹H NMR (300 MHz, DMSO-d6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.85-0.99 (m, 19H), 1.26-1.49 (m, 17H), 1.54-1.58 (m, 10H), 1.83-1.89 (m, 4H), 2.07-2.25 (m, 3H), 2.30-2.78 (m, 4H), 2.81 (m, 2H), 3.63-3.78 (m, 1H), 4.06-4.16 (m, 2H), 5.01-5.30 (m, 2-H), 7.12-7.17 (d, 1H), 7.40-7.50 (m, 1H), 7.70-7.7 (m, 2H), 8.43-8.52 (m, 1H); Mass: 836 [M+1]⁺ 837 (100%); HPLC Purity: 88.6%.

Example 54: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.16 (bs, 11H), 11.71 (bs, 1H), 7.45-7.60 (m, 3H), 7.34 (m, 1H), 6.94 (m, 1H), 5.10 (m, 1H), 4.30 (m, 2H), 3.80 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.6-2.85 (m, 2H), 2.1-2.35 (m, 4H), 0.70-2.0 (m, 48H), 0.24 (m, 2H), 0.13 (m, 1H), −0.06 (m, 1H); Mass (ESI): 912.59 (M+H); HPLC: 93.05%.

Example 55: Preparation of (1R,3S)-3-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a 5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 14.41 (bs, 1H), 12.12 (bs, 1H), 7.78 (m, 2H), 7.69 (s, 1H), 7.36 (m, 2H), 5.12 (m, 1H), 4.35 (m, 2H), 3.90 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 31H), 2.7-3.0 (m, 3H), 2.05-2.40 (m, 4H), 0.70-2.0 (m, 48H), 0.24 (m, 3H), −0.04 (m, 1H); Mass (ESI): 912.73 [M+H]⁺; HPLC: 88.26%.

Example 56: Preparation of (1R,3S)-3-((((R,3aS,5aR,5bR,7aR,9S,111aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.17 (s, 1H), 11.0 (br peak, 1H), 6.51 & 6.35 (s, 1H), 5.0 (m, 1H), 4.37 (m, 1H), 3.5-3.80 (m, 2H), 2.75-3.0 (m, 3H), 2.10-2.60 (m, 4H), 0.60-2.0 (m, 59H), 0.15-0.40 (m, 4H); Mass (ESI): 800.70 [M+1H]⁺; HPLC: 90.94%.

Example 57: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-(4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxycarbonyl) cyclobutane-1-carboxylic acid

¹H NMR (300 MHz, DMSO): δ 7.65 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 7.29-7.21 (m, 2H), 4.48-4.44 (m, 3H), 3.14-3.08 (m, 1H), 2.95-2.76 (m, 4H), 2.65-2.58 (m, 1H), 2.41-2.32 (m, 3H), 2.15-1.92 (m, 8H), 1.48-1.41 (m, 5H), 1.39-1.25 (m, 10H), 1.21-1.16 (m, 3H), 1.09 (s, 3H), 1.03 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.81 (s, 9H), 0.8-0.78 (m, 1H), 0.45-0.28 (m, 2H), 0.27-0.16 (m, 2H); ES Mass: [M]⁺ 834.54; HPLC purity: 90.96%.

Example 58: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

¹H NMR (300 MHz, CDCl₃): δ ppm 4.80-4.62 (m, 1H), 4.52-4.43 (m, 2H), 4.22-4.10 (m, 1H), 3.05-2.95 (m, 1H), 2.88-2.72 (m, 4H), 2.617 (t, J=11.1 Hz, 1H), 2.498 (s, 3H), 2.15-0.78 (m, 60H), 0.60-0.32 (m, 2H), 0.30-0.17 (m, 2H); ES MS: [M+H]⁺ 815.5 (100%); HPLC: 97.4%.

Example 59: Preparation of (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(trifluoro methyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl icosahydro-1H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 0.13-0.15 (m, 1H), 0.25 (m, 2H), 0.81-1.94 (m, 24H), 1.05-1.16 (m, 3H), 1.24-1.26 (m, 8H), 1.32-1.37 (m, 8H), 1.39 (m, 7H), 1.55-1.64 (m, 4H), 1.75-1.92 (m, 4H), 2.07-2.08 (m, 3H), 2.24-2.34 (m, 2H), 2.67-2.82 (m, 3H), 3.57 (bs, 1H), 3.73 (bs, 1H), 4.31-4.37 (t, 1H), 4.97 (bs, 1H), 7.52 (s, 1H), 12.14-12.19 (m, 2H); Mass: [M+H]⁺ 812.52 (100%); HPLC:91.47%.

Example 60: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a 5b,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid

H¹ NMR (DMSO-d₆, 300 MHz): δ 12.16 (bs, 1H), 4.76 (bs, 1H), 4.55 (bs, 1H), 4.45 (bs, 1H), 4.29 (bs, 1H), 3.47 (t, 1H), 2.28 (t, 1H), 3.03 (t, 2H), 2.81 (t, 1H), 2.36 (s, 3H), 2.14 (d, 1H), 1.92 (bs, 6H), 1.80 (m, 3H), 1.62 (d, 4H), 1.46 (s, 5H), 1.35 (m, 10H), 1.16 (bd, 11H), 1.09 (m, 5H), 0.97 (s, 3H), 0.88 (s, 9H), 0.79 (s, 3H), 0.66 (s, 3H), 0.35 (t, 2) and 0.20 (t, 2H); Mass: [M]⁺ 841.58 (100%).

Example 61: Preparation of (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11b,13aR,13bR-3a-((S)-2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.14 (bs, 1H), 11.95 (bs, 1H), 7.48 (m, 1H), 7.41 (m, 1H), 7.09 (m, 2H), 5.10 (m, 1H), 4.37 (m, 1H), 3.82 (m, 1H), 3.65 (m, 1H), 2.70-2.95 (m, 3H), 2.0-2.35 (m, 4H), 0.70-2.0 (m, 50H), 0.05-0.30 (m, 3H), −0.10 (m, 1H); Mass (ESI): 794.63 [M+H]⁺; HPLC: 97.68%.

Example 62: Preparation of 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) butanoic acid

Step 1: Synthesis of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate

To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid (prepared as described in WO 2013/160810 A2, 1.3 g, 2.6 mmol) in DCM (10 ml), Oxalyl chloride (1.1 ml, 8.9 mmol) in DCM (20 ml), 1 drop of DMF was added at 0° C. and stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (20 ml), which was added to the above stirred solution of (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine (Intermediate 1, 0.58 g, 2.7 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, washed with water followed by 1N HCl and brine solution. The organic layer was dried over Na₂SO₄, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 30% EtOAc in hexane) to afford the title compound (wt: 800 mg) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.17-0.24 (m, 2H), 0.40-0.50 (m, 2H), 0.85-0.91 (m, 20H), 1.07-1.51 (m, 131H), 1.53-1.67 (m, 4H), 1.70-1.96 (m, 4H), 2.09 (s, 6H), 2.10-2.85 (s, 3H), 2.95-3.10 (m, 2H), 4.20-4.24 (m, 1H), 5.33 (m, 1H), 7.24-7.29 (m, 2H), 8.05-8.07 (d, 1H), 8.43-8.44 (d, 1H), 8.97 (s, 1H); Mass: 707[M+1]⁺708 (100%).

Step 2: Synthesis of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)methanone

To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8, 11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (step 1, 0.8 g, 1.12 mmol) in MeOH (20 ml) was added potassium carbonate (1.24 g, 9.0 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over Na₂SO₄. Then the solvent was evaporated and the resulting crude was purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (wt: 0.6 g) as an off white solid. ¹H NMR (300 MHz, CDCl₃): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 8H), 1.07-1.26 (m, 101H), 1.29-1.56 (m, 12H), 1.69-1.99 (m, 8H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 5H), 5.31-5.35 (m, 1H), 7.24-7.29 (m, 2H), 8.05-8.07 (d, 1H), 8.43-8.44 (d, 1H), 8.97 (s, 1H); Mass:665 [M+1]⁺ 666 (100%).

Step 3: 2, 2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,1 aR,11bR,13aR,13bR)-5a,5b,8,8, 11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl) icosahydro-H-cyclopenta[a]chrysen-9-yl)oxy) butanoic acid

2,2-Dimethylsuccinic anhydride (0.2 ml, 1.59 mmol) was added to a stirred solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)methanone (step 2, 0.3 g, 0.44 mmol), DMAP (0.10 g, 0.89 mmol) in toluene (15 ml) at room temperature and refluxed for about 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc, washed with water followed by 1N HCl, water and brine solution. The residue was dried over Na₂SO₄, the solvent was evaporated under vacuum and purified by silica gel column (100-200 mesh, elution 5% MeOH/DCM) to afford the title compound (wt: 0.15 g) as an off white solid. ¹H NMR (300 MHz, DMSO-D6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 15H), 0.93 (s, 6H), 1.07-1.26 (m, 9H), 1.29-1.56 (m, 20H), 1.69-1.99 (m, 10H), 2.09-2.18 (m, 4H), 2.23-2.27 (m, 3H), 2.31-2.39 (m, 5H), 2.72 (s, 1H), 3.60-3.76 (m, 2H), 4.36-4.38 (m, 1H), 5.01-5.12 (m, 1H), 7.11-7.22 (m, 1H), 7.20-7.48 (m, 1H), 7.66-7.79 (m 2H), 8.43-8.48 (m 1H), 10.50 (s, 1H); Mass: 794 [M+1]+795 (100%); HPLC Purity: 90.68%.

The following compounds are prepared as described in the above Example-62 procedure with their corresponding intermediates (S)-2-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyridine (Intermediate 1); (S)-5-(3-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 2); (S)-5-(4-(2-methoxyethoxy)phenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 4); (S)-5-(4-fluorophenyl)-2-(pyrrolidin-2-yl)-1H-imidazole (Intermediate 7); 4-(4-fluorophenyl)-2-((2 S,4R)-4-(2-methoxyethoxy)pyrrolidin-2-yl)-1H-imidazole 2,2,2-trifluoroacetate (Intermediate 11); 4-(5-phenyl-1H-imidazol-2-yl)piperidine hydrochloride (Intermediate 25); 4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine (Intermediate 26); (1R,3S,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (Commercially available) to give the corresponding following compounds:

Example 63: Preparation of 3,3-dimethyl-5-oxo-5-(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S-2-(5-pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy) pentanoic acid

¹H NMR (300 MHz, DMSO-D6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 15H), 0.93 (s, 6H), 1.07-1.26 (m, 9H), 1.29-1.56 (m, 20H), 1.69-1.99 (m, 10H), 2.09-2.18 (m, 4H), 2.23-2.27 (m, 3H), 2.31-2.39 (m, 51H), 2.43-2.57 (m, 2H), 2.72 (s, 11H) 3.60-3.76 (m, 2H), 4.36-4.38 (m, 1H), 5.01-5.12 (m, 1H), 7.11-7.22 (m, 1H), 7.20-7.48 (m, 1H), 7.66-7.79 (m 2H), 8.43-8.48 (m, 1H), 10.50 (s, 1H); Mass: 808 [M+1]⁺ 809 (100%); HPLC Purity: 92.68%.

Example 64: Preparation of 5-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 8H), 0.93 (s, 6H), 1.07-1.26 (m, 7H), 1.29-1.56 (m, 10H), 1.57-1.59 (m, 6H) 1.69-1.99 (m, 15H), 2.09-2.18 (m, 4H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 5H), 4.20-4.24 (m, 1H), 5.31-5.35 (m, 1H), 7.22-7.60 (m, 3H), 7.70-7.88 (m, 2H), 10.50 (s, 1H); Mass: 825[M+1]⁺ 826 (100%); HPLC Purity: 98.08%.

Example 65: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid

¹H NMR (300 MHz, DMSO-d6): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 15H), 0.93 (s, 6H), 1.07-1.26 (m, 3H), 1.29-1.56 (m, 18H), 1.57-1.59 (m, 14H), 1.69-1.99 (m, 1H), 2.09-2.18 (m, 3H), 2.19-2.21 (m, 2H), 2.23-3.45 (m, 61H), 3.82-4.13 (m, 3H), 4.20-4.24 (m, 1H), 5.31-5.35 (m, 1H), 7.22-7.60 (m, 3H), 7.70-7.88 (m, 2H), 10.50 (s, 1H); Mass: 811[M+1]⁺ 812 (100%); HPLC Purity: 89.12%.

Example 66: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy-2,2-dimethyl-4-oxobutanoic acid

¹H NMR (300 MHz, CDCl₃): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 15H), 0.93 (s, 4H), 1.16-1.23 (m, 9H), 1.29-1.32 (m, 6H), 1.35-1.66 (m, 20H), 1.62-1.99 (m, 7H), 2.09-2.18 (m, 2H), 2.23-2.45 (m, 4H), 2.46-2.56 (m, 3H), 3.30 (m, 6H), 3.54-3.74 (m, 4H), 4.06-4.09 (m, 3H), 4.12-4.35 (m, 1H), 5.02 (s, 1H), 7.22-7.60 (m, 3H), 7.70-7.88 (m, 2H), 10.50 (s, 1H); Mass: 868 [M+1]⁺; HPLC Purity: 91.09%.

Example 67: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a 5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

H¹ NMR (DMSO-D₆, 300 MHz): δ 12.16 (bs, 1H), 11.61 (bs, 1H), 7.75 (m, 2H), 7.39 (s, 1H), 7.13 (m, 2H), 5.06 (m, 1H), 4.40 (m, 1H), 4.36 (m, 1H), 3.78 (m, 2H), 3.56 (m, 2H), 3.42 (m, 2H), 3.24 (s, 3H), 2.95 (m, 1H), 2.59 (m, 2H), 2.15 (m, 2H), 0.70-2.0 (m, 48H), 0.24 (in, 2H), 0.13 (m, 1H), −0.04 (m, 1H); Mass (ESI): 886.52 [M+H]⁺; HPLC: 92.64%.

Example 68: Preparation of 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-(4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid

¹H NMR (300 MHz, DMSO): δ 12.1 (bs, 2H), 7.7 (d, J=7.2 Hz, 2H), 7.44 (bs, 1H), 7.32 (t, J=7.5 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 4.4-4.23 (m, 3H), 2.98-2.74 (m, 4H), 2.12 (d, J=12.9 Hz, 1H), 2.04-1.92 (m, 4H), 1.73-1.41 (m, 10H), 1.4-1.23 (m, 8H), 1.21-1.0 (m, 13H), 0.96 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H), 0.78 (s, 6H), 0.34 (t, J=7.2 Hz, 2H), 0.18 (t, J=5.7 Hz, 2H); HPLC purity: 87.36%+9.47%.

Example 69: Preparation of 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid

¹H NMR (300 MHz, CDCl₃): δ ppm 4.80-4.62 (m, 1H), 4.57-4.45 (m, 2H), 4.20-4.10 (m, 1H), 3.05-2.95 (m, 1H), 2.92-2.70 (m, 2H), 2.68-2.62 (m, 2H), 2.50 (s, 3H), 2.15-0.75 (m, 59H), 0.50-0.40 (m, 1H), 0.40-0.32 (m, 1H), 0.28-0.15 (m, 2H); ES MS: [M+H]⁺ 789.4 (100%); HPLC: 90%+9.6% (isomers).

Example 70: Preparation of 5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxo

¹H NMR (300 MHz, CDCl₃): δ 0.22-0.25 (m, 2H), 0.26-0.27 (m, 2H), 0.79-0.93 (m, 131H), 0.93 (6H), 1.07-1.26 (m, 10H), 1.29-1.56 (m, 12H), 1.69-1.99 (m, 8H), 2.09-2.18 (m, 41H), 2.23-3.45 (m, 6H), 3.82-4.13 (m, 5H), 4.20-4.24 (m, 1H), 5.31-5.35 (m, 1H), 7.22-7.60 (m, 3H), 7.70-7.88 (m, 2H), 10.50 (s, 1H); Mass: 825 [M+1]⁺ 826 (100%). HPLC Purity: 94.10%.

Example 71: Preparation of 4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

¹H NMR (300 MHz, Pyridine-d5+D₂O): δ ppm 5.28-5.12 (m, 1H), 4.80-4.55 (m, 3H), 3.28-3.02 (m, 2H), 3.0-2.82 (m, 2H), 2.63 (s, 3H), 2.30-2.05 (m, 4H), 2.05-1.60 (m, 14H), 1.58-1.40 (m, 16H), 1.40-1.17 (m, 9H), 1.05 (s, 6H), 0.95 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H), 0.82-0.70 (m, 1H), 0.76 (s, 3H), 0.55-0.45 (m, 1H), 0.45-0.35 (m, 1H), 0.30-0.18 (m, 2H); ESI-MS: m/z 815.49 (M+H)⁺.

Example 72: Preparation of 5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a 5b,8,8,11a-pentamethyl-1-(-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid

H¹ NMR (DMSO-d₆, 300 MHz): δ 12.02 (bs, 1H) 4.76 (bs, 1H), 4.55 (bs, 1H), 4.45-4.37 (m, 2H), 3.05-3.01 (m, 2H), 2.82 (d, 1H), 2.40 (s, 3H), 2.28 (s, 3H), 1.94-1.76 (m, 5H), 1.68-1.36 (m, 6H), 1.31 (d, 5H), 1.30 (m, 6H), 1.11 (s, 6H), 1.05 (s, 3H), 0.90 (m, 6H), 0.83 (m, 6H), 0.81 (s, 9H), 0.36 (t, 2H) and 0.32 (t, 2H); Mass: [M]⁺ 829.48 (100%).

Pharmacological Activity

The compounds described herein can be tested for their antiviral activity following procedures known to a person of ordinary skill in the art. For example, the following protocols can be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.

Example 53: Evaluation of Compounds Antiviral Activity

MT-2 cells were infected with required number of TCID50's of HIV-1 strains, for e.g., 92HT599. The infected cells were plated at the concentration of 30, 000 cells per well in a 96 well plate. Test compound was added to the 96 well plate with the final concentration of DMSO (vehicle—not more than 1%). The plates are then incubated in a CO₂ incubator for ˜96 hours (˜4 days) for viral infection. At the end of incubation period an aliquot from each well was taken for p24 estimation. The quantitation of p24 is an estimated index for antiviral activity of the compound. Percent inhibition was calculated with reference to control values (vehicle controls).

p-24 estimation was carried out using Advance biosciences kit as per the procedure detailed by supplier.

Results:

TABLE 1 Antiviral activity Antiviral activity Compound (% inhibition) Compound (% inhibition) No. 1 μM 0.1 μM No. 1 μM 0.1 μM 42 73 63 29 99 99 5 100 0 30 99 61 54 93 13 31 100 100 2 97 0 32 99 60 40 99 29 34 100 86 25 99 89 35 100 100 70 99 84 36 100 98 37 99 99 59 100 71 28 99 54 61 100 100 A Antiviral activity Antiviral activity Compound IC₅₀ (nM) Compound IC₅₀ (nM) No. Efficacy IC50 (nM) No. Efficacy IC50 (nM) 21 1.29 55 1.037 23 0.7 8 61.14 57 4.415 14 0.138 68 12.75 4 1.669 11 5.96 65 15.67 12 139.3 64 14.62 62 0.8 10 2.823 63 3.6 46 10.98 48 5.8 47 15.61 13 4.9 1 8.064 7 5.5 20 58.41 9 5.522 15 124.1 24 9.06 16 102.8 43 0.3 17 58.62 67 0.44 18 35.77 45 0.3 56 56.25 66 0.73 22 1000 50 0.35 44 27.63 51 43.29 32 23.34 37 3.21 34 6.662 28 19.36 35 2.814 29 12.27 36 1.224 30 89.58 59 55.41 31 19.73 61 56.91

Example 54: Evaluation of Compounds Cyto-Toxicity (MTT Assay)

On day 1 calculate the number of cells required for the assay and seed 3×10⁴ cells in 200 μl per well. Weigh the compound and dissolve it in DMSO to get 10 mM stock which is further diluted to 3 mM and 1 mM. The drugs from these stocks were added to plate to get final concentration of 100 μM, 30 μM and 10 μM. Add DMSO to controls in a way to obtain final concentration of solvent that is not greater than 1%. Incubate for 4 days in 5% CO₂ incubator at 37° C. On day 4, 100 μl of medium was removed from each well without disturbing the cells. Add 10 μl of MTT reagent and incubate for 4 hours at 5% CO₂ incubator at 37° C. for formation of crystals. Add 200 μl of 0.1N acidic isopropanol to dissolve the crystals and read the plate at 590 nm.

Results:

TABLE 2 Cytotoxicity Compound % viability No. 100 μM 30 μM 10 μM 5 98 100 100 54 6 16 49 2 5 31 64 40 25 48 80 25 11 32 65 A Cytotoxicity Compound % viability No. 1 nM 0.1 nM 42 94 94

Example 55: Evaluation of Compounds Single Dose Oral Pharmacokinetic Stud

The test item was administered through oral route to animals (rat/mice) at 30 mg/kg dose in a suitable vehicle at 10 ml/kg dose volume. Blood samples (˜50 uL at each time point) were collected from retro-orbital plexus using K3 EDTA as anticoagulant in eppend; orf tubes at defined time intervals under light ether anesthesia. The samples were centrifuged at 3500×g to separate plasma and stored at −80° C. until analysis.

Sample analysis: Test samples were analyzed using LC-MS-MS after developing fit-for-purpose method for each of test compound.

Results:

TABLE 3 Mice oral PK Mice oral PK Com- @30 mg/kg Com- @30 mg/kg pound Cmax AUC 0-t pound Cmax AUC 0-t No. μg/mL μg · hr/mL No. μg/mL μg · hr/mL 21 12.965 268.813 51 4.93 159.818 23 10.614 301.969 55 14.285 381.113 69 16.714 237.5695 8 41.2835 1237.2785 58 3.051 103.987 14 19.648 437.258 57 2.792 66.413 39 5.692 80.934 68 2.018 23.495 4 14.768 398.304 11 16.288 403.034 65 13.31 202.995 12 13.208 395.393 64 5.252 104.598 52 9.611 273.271 10 17.867 300.93 62 7.1175 93.1385 46 8.708 153.428 63 4.466 119.885 53 14.71 470.791 48 20.792 298.911 47 6.819 62.666 7 12.75 341.5 1 6.287 177.248 24 12.19 438.78 15 6.513 208.211 43 15.368 332.584 16 7.891 229.148 67 12.261 246.819 17 7.093 218.989 45 11.502 275.163 18 16.436 409.014 66 6.593 62.119 56 12.041 375.318 41 14.481 257.95 6 3.1 93.43 50 13.869 357.974 19 7.5 183.1 49 10.848 111.0 29 4.5 57.5 38 7.347 127.0 31 9.2 195.0 71 15.8 298.2 32 13.9 315.7 60 6.52 295.4 34 18.7 417.4 70 10.0 171.8 35 14.0 249.9 37 16.8 486.8 36 10.8 157.9 28 10.0 248.0 59 15.7 451.1

REFERENCES

-   1. Antiviral methods and protocols (Eds: D Kinchington and R F     Schinazi) Humana Press Inc., 2000 -   2. HIV protocols (Eds: N L Michael and J H Kim) Humana Press Inc,     1999 -   3. DAIDS Virology manual for HIV laboratories, Publication     NIH-97-3838, 1997 -   4. HIV-1 p24 antigen capture assay, enzyme immunoassay for detection     of Human immunodeficiency Virus Type 1 (HIV-1) p24 in tissue culture     media—Advanced bio science laboratories, Inc kit procedure.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference. 

1. A compound of the formula (1):

wherein, R₁ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl,

(wherein R_(b) is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl); R₂ is H, substituted or unsubstituted alkyl, substituted or unsubstituted aminoacids, substituted or unsubstituted alkoxy or substituted or unsubstituted cycloalkyl; X is absent, O, S, CH₂ or NR_(a) (wherein R_(a) is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or R_(a) can be with their adjacent N and Carbon together form N-contained heterocycle (Preferably, pyrrolidine, piperdine, piperzine, or morpholine); R₃ and R₄ are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted aminoacids and preferably amino acids are substituted by substituted or unsubstituted alkyl, phosphoric acid, or phosphorus prodrugs or R₃ and R₄ are together with their adjacent carbons to form a bond or R₃ and R₄ are together with their adjacent carbons to form cyclopropyl or R₃ and R₄ are together with their adjacent carbons to form epoxide; W is C(O), C(S), or CR₇R₈; R_(x) is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl and specifically heterocycles are imidazoles, oxazoles, oxadiazoles, triazoles, thiazoles, thiadizoles, isothiazoles, isothiadiazoles, pyridines, pyrazines, pyrimidines, or pyridazines; R_(c) is hydrogen or substituted or unsubstituted alkyl; R₆ is H, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy; R_(c) and R₆ on different carbon atoms to form a bond; R₅, R₇ and R₈ are independently selected from H, CO₂R_(d) (wherein R_(d) is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl; ‘n’ is an integer from 1 to 3; including pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or combination thereof.
 2. The compound of claim 1, wherein W is —C(O)—.
 3. A compound of the formula (1A):

wherein, R₁ is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl,

 (wherein R_(b) is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl); R₂ is H, substituted or unsubstituted alkyl, substituted or unsubstituted aminoacids, substituted or unsubstituted alkoxy or substituted or unsubstituted cycloalkyl; X is absent, O, S, CH₂, or NR_(a) (wherein R_(a) is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or R_(a) is with their adjacent N and Carbon together form N-contained heterocycle (Preferably, pyrrolidine, piperdine, piperzine, or morpholine); R₃ and R₄ are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted aminoacids and preferably amino acids are substituted by substituted or unsubstituted alkyl, phosphoric acid, or phosphorus prodrugs or R₃ and R₄ can be together with their adjacent carbons to form a bond or R₃ and R₄ are together with their adjacent carbons to form cyclopropyl or R₃ and R₄ are together with their adjacent carbons to form epoxide; W is C(O), C(S), or CR₈R₉; R₆ is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl and most preferably alkyl is methyl, ethyl, isopropyl, and t-butyl, most preferably aryl is substituted or unsubstituted phenyl, most preferably heteroaryl is pyridine and R₆ is preferably substituted or unsubstituted isopropyl, t-butyl, phenyl, pyridine, pyrazine, pyrimidine or chromene; R₅, R₈ and R₉ are independently selected from H, CO₂R_(d) (wherein R_(d) is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl; R₇ is H, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy; ‘n’ is an integer from 1 to 3; including pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or combination thereof.
 4. The compound of claim 3, wherein W is —C(O)—.
 5. A compound selected from the group consisting of: (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyri din-3-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-ethoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclo butane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy)-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-(2-methoxyethoxy)-2-(4-(pyridin-3-yl)-H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)oxazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl) icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3 aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-methyl-4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-isopropyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyloxazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(tert-butyl)oxazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)Icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(4-phenyloxazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-chloro phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,1 aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3R)-2,2-dimethyl-3-(2-oxo-2-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)ethyl)cyclo butane-1-carboxylic acid, 2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)-icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclopropane-1-carboxylic acid, 2-methyl-2-(4-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)phenoxy)propanoic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-3a-((S)-2-(4-(3-fluoro-4-methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-3-((((R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(2,4-difluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(2-fluoro phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(3-chloro phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-hydroxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-iso propoxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(tert-butyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-4-methoxy-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-methoxypyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4,5-dimethyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl) icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8, 11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid, 4-(((1R,3 aS,5 aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-3a-((S)-2-(5-(3-fluoro-4-methylphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-3a-((S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bS)-1-(1,2-dihydroxypropan-2-yl)-5a,5b,8,8,11a-pentamethyl-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl) icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-3a-((2S,4R)-4-(2-methoxy ethoxy)-2-(4-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8, 8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 4-(((1R,3 aS,5 aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluoro phenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluoro phenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9 S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-methoxy phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8, 11a-pentamethyl-3a-((S)-3-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid, 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8, 11a-pentamethyl-3a-((S)-2-(5-phenyl-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluoro phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,1 aR,11bR,13aR,13bR)-5a,5b, 8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-(2-methoxyethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, 3-(2-((S)-1-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-(((1 S,3R)-3-carboxy-2,2-dimethylcyclobutane-1-carbonyl)oxy)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl) pyridine 1-oxide, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(3-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,1 aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(4-(tert-butyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8, 1a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-(4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methyl cyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane-1-carboxylic acid, (1R,3S)-2,2-dimethyl-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)cyclo butane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, (1R,3S)-3-((((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl) icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid, 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid, 3,3-dimethyl-5-oxo-5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-(pyridin-2-yl)-1H-imidazol-2-yl) pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)pentanoic acid, 5-(((1R,3 aS,5 aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(3-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((S)-2-(5-(4-(2-methoxy ethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxo butanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2S,4R)-2-(4-(4-fluoro phenyl)-1H-imidazol-2-yl)-4-(2-methoxyethoxy)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 2,2-dimethyl-4-oxo-4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8, 11a-pentamethyl-1-(1-methylcyclopropyl)-3a-(4-(5-phenyl-1H-imidazol-2-yl)piperidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)butanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid, 5-(((1R,3 aS,5 aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-3a-((S)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid, 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid and 5-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3R,5S)-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carbonyl)-5a,5b,8,8,11a-penta methyl-1-(1-methylcyclopropyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-3,3-dimethyl-5-oxopentanoic acid and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, ester prodrugs, or combination thereof.
 6. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient.
 7. The pharmaceutical composition according to claim 6, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
 8. A method for preventing, ameliorating or treating a viral mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim
 1. 9. The method according to claim 8, wherein the viral mediated disease, disorder or syndrome is HIV infection, HBV infection, HCV infection.
 10. A method of treating HIV in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim
 1. 11. A method for preventing, ameliorating or treating an HIV mediated disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim
 6. 12. The method according to claim 11, wherein the HIV mediated disease is HIV infection, HBV infection, or HCV infection.
 13. A pharmaceutical composition comprising a compound according to claim 5 and at least one pharmaceutically acceptable excipient.
 14. A method for preventing, ameliorating or treating a viral mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim
 5. 15. A method of treating HIV in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim
 5. 